U.S. patent application number 15/431054 was filed with the patent office on 2017-07-27 for amino acid conjugates of quetiapine, process for making and using the same.
The applicant listed for this patent is KemPharm, Inc.. Invention is credited to Sanjib Bera, Sven Guenther, Travis Mickle.
Application Number | 20170209586 15/431054 |
Document ID | / |
Family ID | 44226775 |
Filed Date | 2017-07-27 |
United States Patent
Application |
20170209586 |
Kind Code |
A1 |
Mickle; Travis ; et
al. |
July 27, 2017 |
AMINO ACID CONJUGATES OF QUETIAPINE, PROCESS FOR MAKING AND USING
THE SAME
Abstract
The presently described technology provides a novel class of
prodrugs of quetiapine that can be synthesized by chemically
conjugating amino acids, such as Lysine to quetiapine. The present
technology also provides methods of treating patients,
pharmaceutical compositions and methods of synthesizing conjugates
of the present technology.
Inventors: |
Mickle; Travis; (Coralville,
IA) ; Guenther; Sven; (Coralville, IA) ; Bera;
Sanjib; (Blacksburg, VA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
KemPharm, Inc. |
Celebration |
FL |
US |
|
|
Family ID: |
44226775 |
Appl. No.: |
15/431054 |
Filed: |
February 13, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14216342 |
Mar 17, 2014 |
9597403 |
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15431054 |
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13518981 |
Jul 23, 2012 |
8715699 |
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PCT/US2010/061853 |
Dec 22, 2010 |
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14216342 |
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61291576 |
Dec 31, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/32 20180101;
A61K 31/553 20130101; A61K 31/554 20130101; A61P 25/24 20180101;
A61P 25/00 20180101; A61P 25/18 20180101; A61K 47/542 20170801;
C07D 267/18 20130101; A61P 25/20 20180101; A61P 43/00 20180101;
A61K 9/0053 20130101; A61P 25/22 20180101; A61K 45/06 20130101;
A61P 25/14 20180101 |
International
Class: |
A61K 47/48 20060101
A61K047/48; A61K 9/00 20060101 A61K009/00; A61K 45/06 20060101
A61K045/06; A61K 31/554 20060101 A61K031/554; A61K 9/48 20060101
A61K009/48; C07D 513/04 20060101 C07D513/04; A61K 9/20 20060101
A61K009/20 |
Claims
1. A composition for treating a psychiatric disorder in a subject
comprising
2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol
(quetiapine) conjugated to lysine via an ester bond, a
pharmaceutically acceptable salt of the conjugate, or their
combination.
2. The composition of claim 1, wherein the composition is
formulated for oral, parenteral, or suppository administration.
3. The composition of claim 2, wherein the composition formulated
for oral administration is selected from the group consisting of a
tablet, capsule, caplet, pill, troche, lozenge, liquid solution,
suspension, elixir, powder, syrup, dragee, gel, slurry, granule,
wafer, and oral thin film.
4. The composition of claim 1, wherein the conjugate is present in
an amount of between about 1 mg and about 2000 mg per unit
dose.
5. The composition of claim 3, wherein the conjugate is present in
an amount of between about 150 and about 800 mg per unit dose.
6. The composition of claim 5, wherein the presence of quetiapine
is based on molar equivalent of unconjugated quetiapine.
7. The composition of claim 1, further comprising one or more of:
lithium, divalproex, adjuvants, antiadherents, binders, coatings,
disintegrants, fillers, flavors and colors, glidants, lubricants,
preservatives, sorbents, sweeteners or a combination thereof.
8. (canceled)
9. The composition of claim 8, wherein the pharmaceutically
acceptable salt is selected from the group consisting of a
hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a
sulfate, a phosphate, an organic acid salt, a nitrate, a benzoate,
and mixtures thereof.
10. The composition of claim 9, wherein the organic acid salt is
selected from the group consisting of a mesylate salt, a besylate
salt, a tosylate salt, an oxalate salt, a fumarate salt, a triflate
salt, a citrate salt, a malate salt, a tartrate salt, or mixtures
thereof.
11. A composition for treating schizophrenia in a subject
comprising a conjugate of quetiapine, an active metabolite of
quetiapine or derivatives of quetiapine conjugated to lysine
wherein the conjugate is represented by any one of the following
structures: ##STR00014##
12. The composition of claim 11, wherein the composition comprises
a pharmaceutically acceptable salt of the conjugate.
13. The composition of claim 12, wherein the pharmaceutically
acceptable salt is selected from the group consisting of a
hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a
sulfate, a phosphate, an organic acid salt, a nitrate, a benzoate,
and mixtures thereof.
14. The composition of claim 13, wherein the organic acid salt is
selected from the group consisting of a mesylate salt, a besylate
salt, a tosylate salt, an oxalate salt, a fumarate salt, a triflate
salt, a citrate salt, a malate salt, a tartrate salt, or mixtures
thereof.
15. The composition of claim 1, wherein the conjugate is a
prodrug.
16. The composition of claim 15, wherein the composition comprises
a pharmaceutically acceptable salt of the prodrug.
17. The composition of claim 11, wherein the conjugate is a
prodrug
18. The composition of claim 17, wherein the composition comprises
a pharmaceutically acceptable salt of the prodrug.
19. A method of treating schizophrenia comprising a step of
administering to a subject a composition comprising a
therapeutically effective amount of
2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethano-
l (quetiapine) conjugated to lysine via an ester bond or a
pharmaceutically acceptable salt thereof.
20. A composition comprising
2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol
(quetiapine) conjugated to lysine via an ester bond, a salt of the
conjugate, or their combination.
21. The composition of claim 20, wherein the salt is a
pharmaceutically acceptable salt.
22. The composition of claim 21, wherein the composition has a
higher relative bioavailability than non-conjugated quetiapine when
administered orally.
23. The composition of claim 21, wherein the composition is
formulated for oral, suppository, or parenteral administration.
24. The composition of claim 23, wherein the composition formulated
for oral administration is selected from the group consisting of a
tablet, capsule, caplet, pill, troche, lozenge, liquid solution,
suspension, elixir, powder, syrup, dragee, gel, slurry, granule,
wafer, and oral thin film.
25. The composition of claim 21, wherein the conjugate is present
in an amount of between about 1 mg and about 2000 mg per unit
dose.
26. The composition of claim 24, wherein the conjugate is present
in an amount of between about 150 and about 800 mg per unit
dose.
27. The composition of claim 25, wherein the presence of quetiapine
is based on molar equivalent of unconjugated quetiapine.
28. The composition of claim 26, wherein the presence of quetiapine
is based on molar equivalent of unconjugated quetiapine.
29. The composition of claim 21, further comprising one or more of:
lithium, divalproex, adjuvants, antiadherents, binders, coatings,
disintegrants, fillers, flavors and colors, glidants, lubricants,
preservatives, sorbents, sweeteners, or a combination thereof.
30. The composition of claim 21, wherein the salt is selected from
the group consisting of a hydrochloride salt, a hydrobromide salt,
a hydroiodide salt, a sulfate, a phosphate, an organic acid salt, a
nitrate, a benzoate, and mixtures thereof.
31. The composition of claim 30, wherein the organic acid salt is
selected from the group consisting of a mesylate salt, a besylate
salt, a tosylate salt, an oxalate salt, a fumarate salt, a triflate
salt, a citrate salt, a malate salt, a tartrate salt, and mixtures
thereof.
32. The composition of claim 20, wherein the conjugate is a
prodrug.
33. The composition of claim 32, wherein the composition comprises
a pharmaceutically acceptable salt of the prodrug.
34. A composition comprising a conjugate of quetiapine, an active
metabolite of quetiapine or derivatives of quetiapine conjugated to
lysine wherein the conjugate is represented by any one of the
following structures: ##STR00015##
35. The composition of claim 34, wherein the salt is a
pharmaceutically acceptable salt.
36. The composition of claim 35, wherein the salt is selected from
the group consisting of a hydrochloride salt, a hydrobromide salt,
a hydroiodide salt, a sulfate, a phosphate, an organic acid salt, a
nitrate, a benzoate, and mixtures thereof.
37. The composition of claim 36, wherein the organic acid salt is
selected from the group consisting of a mesylate salt, a besylate
salt, a tosylate salt, an oxalate salt, a fumarate salt, a triflate
salt, a citrate salt, a malate salt, a tartrate salt, or mixtures
thereof.
38. The composition of claim 34, wherein the conjugate is a
prodrug.
39. The composition of claim 38, wherein the composition comprises
a pharmaceutically acceptable salt of the prodrug.
40. A compound represented by one of the following structures:
##STR00016##
Description
RELATED APPLICATIONS
[0001] This application claims priority to and is a divisional
application of U.S. application Ser. No. 14/216,342, filed on Mar.
17, 2014, which claims priority to and is a continuation of U.S.
application Ser. No. 13/518,981, filed on Jul. 23, 2012, which is a
national stage entry of PCT/US10/61853, filed on Dec. 22, 2010,
which claims priority to and benefit from U.S. Provisional
Application Ser. No. 61/291,576, filed on Dec. 31, 2009, the
contents of all of which are incorporated herein by reference in
their entireties.
BACKGROUND OF THE INVENTION
[0002] Quetiapine has been used in the treatment of severe mental
illness in approximately 70 countries including the US, Canada,
most Western European countries, and Japan. Quetiapine is a
dibenzothiazepine derivative with a relatively broad receptor
binding profile. It has major affinity to cerebral serotonergic
(5-HT.sub.2A), histaminergic (H1), and dopaminergic D.sub.1 and
D.sub.2 receptors, moderate affinity to .alpha..sub.1- and
.alpha..sub.2-adrenergic receptors, and minor affinity to
muscarinergic M1 receptors; it demonstrates a substantial
selectivity for the limbic system. This receptor avidity profile
with relatively higher affinity for the 5-HT.sub.2A receptor
compared to the D.sub.2 receptor is considered to be, at least in
part responsible for the antipsychotic characteristics and low
incidence of extrapyramidal side-effects of quetiapine.
[0003] The efficacy of quetiapine in reducing positive and negative
symptoms of schizophrenia has been proven in several clinical
trials with placebo-controlled comparators. Quetiapine has also
demonstrated robust efficacy for treatment of cognitive,
anxious-depressive, and aggressive symptoms in schizophrenia.
Quetiapine has also proven efficacy and tolerability in the
treatment of moderate to severe manic episodes, and in the
treatment of juveniles with oppositional-defiant or conduct
disorders, and in the treatment of the geriatric population with
dementia. Data indicate that quetiapine is also effective in the
treatment of bipolar depressive symptoms without increasing the
risk of triggering manic episodes, and in the treatment of
borderline personality disorder. In comparison with other atypical
antipsychotics, quetiapine has a favorable side-effect profile.
[0004] In clinical trials, only small insignificant prolongations
of the QT interval were observed. Weight-gain liabilities and
new-onset metabolic side-effects occupy a middle-ground among newer
antipsychotics. As a result of its efficacy and tolerability
profile, quetiapine has become well established in the treatment of
schizophrenia and other psychiatric disorders.
[0005] Recently though, in addition to large interindividual
variability and weight gain, reports surfaced on treatment emergent
diabetes (TED), associated with chronic administration of
quetiapine. Additionally, the therapeutical dose of quetiapine is
relatively high, forcing the production of pharmaceutical
compositions with relatively high concentrations of the active
ingredient (up to 60%). Making tablets of such a high concentration
of the active pharmaceutical ingredient (API) is difficult,
particularly due to the bad tableting properties of the API.
[0006] An advantageous alternative would therefore be to improve
the drug's bioavailability, leading to an improved formulation that
can lower the total necessary therapeutical dose and/or reduce
side-effects such as TED and/or weight gain, and avoid the need for
repeated administration. That formulation would help maintain
regimen adherence by otherwise reluctant psychiatric patients.
BRIEF SUMMARY OF THE INVENTION
[0007] The present technology is directed to a novel class of
prodrugs of quetiapine that can be synthesized by chemically
conjugating amino acids to quetiapine. The chemical bond between
these two moieties is established in one aspect, by reacting a
primary hydroxyl functionality of quetiapine or any one of its
active metabolites and/or derivatives, with the carboxyl group of
the amino acids, thereby creating a carboxylic ester conjugate.
[0008] In one embodiment, the invention provides a composition for
treating a psychiatric disorder such as schizophrenia, bipolar
disorder, obsessive-compulsive disorder, post-traumatic stress
disorder, restless legs syndrome, autism, alcoholism, depression,
insomnia or Tourette syndrome in a subject, comprising a conjugate
of
2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol
(quetiapine, QTP) or an active metabolite and/or active derivative
thereof; and a standard amino acid such as an aliphatic or aromatic
amino acid, non-standard amino acid or synthetic amino acid, a salt
thereof, or a combination thereof. In another embodiment, the
composition is formulated for oral or rectal administration wherein
quetiapine or its active metabolite and/or active derivative
thereof such as 7-hydroxy-N-desalkyl-quetiapine (7-OH-norQTP;
4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazine and a
standard amino acid such as an aromatic or aliphatic amino acids,
non-standard amino acid or synthetic amino acid, a salt thereof, a
derivative thereof or their combination is present in the
composition in an amount of about 1-2000 mg/dose based on equimolar
weight of unconjugated quetiapine, or unconjugated active
metabolite and/or active derivative thereof. Oral administration is
carried out in certain embodiments using a tablet, capsule, caplet,
pill, troche, lozenge, liquid solution, suspension, elixir, or oral
thin film (OTF).
[0009] In another embodiment, the invention provides quetiapine or
its active metabolite, conjugated to a standard amino acid, i.e.,
valine as represented by any one of the structures of formulas
I-IV, a pharmaceutically acceptable salt thereof such as a
phosphate salt, a derivative thereof or their combination.
##STR00001##
[0010] In one embodiment, the invention provides quetiapine or its
active metabolite, conjugated to a standard amino acid i.e.,
phenylalanine as represented by any one of the structures of
formulas V-VIII, a pharmaceutically acceptable salt thereof such as
a hydrochloride salt, phosphate salt, mesylate salt or a besylate
salt, a derivative thereof or their combination.
##STR00002##
[0011] In another embodiment, the invention provides quetiapine or
its active metabolite, conjugated to a standard amino acid, i.e.,
lysine as represented by any one of the structures of formulas
IX-XII, a pharmaceutically acceptable salt thereof such as a
phosphate salt, a derivative thereof or their combination.
##STR00003##
[0012] In another embodiment, the invention provides a method of
conjugating quetiapine or its active metabolite and/or active
derivative thereof such as 7-hydroxy-quetiapine (7-OH-QTP) and a
standard amino acid such as an aromatic or aliphatic amino acids,
non-standard amino acid such as homoarginine or synthetic amino
acid, comprising the steps of: in the presence of a base such as
4-methylmorpholine (NMM), 4-(dimethylamino)pyridine (DMAP),
attaching an amine-protected amino acid such as an aliphatic or
aromatic amino acid to quetiapine or its active metabolite and/or
active derivative, whereby the amine moiety is protected with
tert-butyloxycarbonyl (Boc) in one embodiment; followed by
deprotecting the amine-protected amino acid moiety, alone or either
sequentially or simultaneously with deprotecting the amino acid
side chain that may be protected as well, thereby conjugating
quetiapine or its active metabolite and/or active derivative
thereof and an amino acid.
[0013] In one embodiment, the invention provides a method of
increasing the relative bioavailability of quetiapine or its active
metabolite and/or active derivative thereof such as
N-desalkyl-quetiapine (norQTP), 7-OH-norQTP or 7-OH-QTP, comprising
the step of conjugating the quetiapine or the active metabolite
and/or active derivative thereof to a standard amino acid such as
an aromatic or aliphatic amino acids, non-standard amino acid such
as homoarginine or synthetic amino acid, thereby modulating the
hydrophobicity, solubility, improving absorption, altering
metabolic pathways or their combination, resulting in certain
embodiments, in a higher C.sub.max and/or AUC and/or longer or
similar T.sub.max values produced by unconjugated quetiapine when
administered at equimolar doses. Increased bioavailability may also
result in: reduced interindividual variability in plasma
concentrations; decrease the number and/or amount of active,
inactive, toxic or non-toxic metabolites; and increase the number
and/or amount of active metabolites produced by unconjugated
quetiapine or its active metabolite and/or active derivative
thereof.
[0014] In another embodiment, the invention provides a method of
treating a psychiatric disorder requiring the binding of dopamine
receptor(s), serotonin receptor(s), or histamine receptor(s) or a
combination thereof in a subject such as human or mammal,
comprising the step of orally or rectally administering to the
subject a composition comprising a therapeutically effective amount
of about 1-2000 mg/dose based on equimolar weight of unconjugated
API of quetiapine or its active metabolite and/or active derivative
thereof such as N-desalkyl-quetiapine,
7-hydroxy-N-desalkyl-quetiapine, or 7-hydroxy-quetiapine,
conjugated to a standard amino acid such as an aromatic or
aliphatic amino acids, non-standard amino acid or synthetic amino
acid, a pharmaceutically acceptable salt or derivative thereof,
thereby binding a dopamine receptor, a serotonin receptor,
histamine receptor or any combination permutation thereof. In one
embodiment, the invention provides a method of treating
schizophrenia or bipolar disorder in a subject in need thereof,
comprising the step of administering to the subject a composition
comprising a therapeutically effective amount of a quetiapine or
its active metabolite and/or active derivative thereof such as
N-desalkyl-quetiapine, 7-hydroxy-N-desalkyl-quetiapine, or
7-hydroxy-quetiapine, conjugated to an amino acid, a
pharmaceutically acceptable salt such as a phosphate salt, or
derivative thereof, thereby binding to a dopamine receptor, a
serotonin receptor, or both and treating schizophrenia or bipolar
disorder.
[0015] In one embodiment, the invention provides a method of
reducing weight gain resulting from chronic or acute administration
of quetiapine in a subject, comprising the step of orally or
rectally administering to the subject a composition comprising
therapeutically effective amount of about 1-2000 mg/dose based on
equimolar weight of unconjugated API of a quetiapine or its active
metabolite and/or active derivative thereof such as
N-desalkyl-quetiapine, 7-hydroxy-N-desalkyl-quetiapine, or
7-hydroxy-quetiapine, conjugated to a standard amino acid such as
an aromatic or aliphatic amino acids, non-standard amino acid such
as homoarginine or synthetic amino acid, a pharmaceutically
acceptable salt thereof such as a phosphate salt, or a derivative
thereof, thereby modulating leptin and/or gherlin levels in the
subject and reducing, decreasing and/or inhibiting weight gain in
the subject.
[0016] In one embodiment, the invention provides a method of
reducing weight gain resulting from chronic or acute administration
of quetiapine in a subject, comprising the step of orally or
rectally administering to the subject a composition comprising a
therapeutically effective amount of about 1-2000 mg/dose based on
equimolar weight of unconjugated API of a quetiapine or its active
metabolite and/or active derivative thereof such as
N-desalkyl-quetiapine, 7-hydroxy-N-desalkyl-quetiapine, or
7-hydroxy-quetiapine, conjugated to a standard amino acid such as
an aromatic or aliphatic amino acids, non-standard amino acid such
as homoarginine or synthetic amino acid, a pharmaceutically
acceptable salt thereof such as a phosphate salt, or a derivative
thereof, thereby altering the metabolism of quetiapine, its
metabolite(s) and/or derivative(s) resulting in reduced binding to
histamine receptors.
[0017] In another embodiment, the invention provides for the use of
a therapeutically effective amount of a conjugate of quetiapine,
its active metabolite and/or active derivative and/or their
combination; and a standard, non-standard and/or synthetic amino
acid and their combination; in a medicament for the treatment of a
disorder associated with serotonin, dopamine or histamine
dysfunction in a subject in need thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] The invention will be better understood from a reading of
the following detailed description taken together with the figures
and examples provided herein wherein like reference designators are
used to designate like elements or findings, and in which:
[0019] FIG. 1 shows general structure of standard amino acids;
[0020] FIG. 2 shows general structure of non-standard amino
acids;
[0021] FIG. 3A and FIG. 3B show synthetic amino acids;
[0022] FIG. 4 shows the oral PK profile of quetiapine released from
valine-quetiapine compared to an equimolar dose of quetiapine
dihydrochloride in rats;
[0023] FIG. 5 shows the oral PK profiles of quetiapine released
from .beta.-alanine-quetiapine, phenylalanine-quetiapine and
lysine-quetiapine compared to an equimolar dose of quetiapine
dihydrochloride in rats;
[0024] FIG. 6 shows the oral PK profiles of quetiapine released
from tyrosine-quetiapine, leucine-quetiapine and
aspartate-quetiapine compared to an equimolar dose of quetiapine
dihydrochloride in rats;
[0025] FIG. 7 shows a schematic of the process of synthesis of the
valine-quetiapine conjugate;
[0026] FIG. 8 shows embodiments of valine conjugates; and
[0027] FIG. 9 shows embodiments of phenylalanine conjugates.
DETAILED DESCRIPTION OF THE INVENTION
[0028] In one embodiment, the invention is directed to quetiapine
conjugate compositions, their synthesis and use. In another
embodiment, the invention is directed to quetiapine conjugates with
standard, non-standard or synthetic amino acids, their syntheses
and use in therapeutic compositions for the treatment of
psychiatric disorders.
[0029] Quetiapine:
##STR00004##
is an atypical antipsychotic in the sub-class of multi-acting
receptor-targeted antipsychotics (MARTA). Quetiapine exhibits
antagonist activity at the dopamine D.sub.2 and D.sub.1 receptors,
the serotonin 5-HT.sub.2 receptor, the adrenergic .alpha..sub.1 and
.alpha..sub.2 receptors and the histamine H.sub.1 receptor. While
the modulation of the dopamine and serotonin receptors are thought
to be responsible for the therapeutic activity of quetiapine, its
affinity to the histamine and adrenergic receptors may be the cause
of some of its side-effects, particularly its somnolent and
hypotensive effects.
[0030] Quetiapine is currently approved for the following
indications: [0031] Acute and chronic treatment of schizophrenia.
[0032] Acute depressive episodes associated with bipolar disorder.
[0033] Acute manic or mixed episodes associated with bipolar I
disorder as monotherapy and as an adjunct to lithium or divalproex
therapy. [0034] Chronic treatment of bipolar I disorder as adjunct
therapy to lithium or divalproex.
[0035] Quetiapine has also shown acceptable efficacy in some
off-label indications that include obsessive-compulsive disorder,
post-traumatic stress disorder, restless legs syndrome, autism,
alcoholism, depression and Tourette syndrome. It has been used as
sedative for patients with sleep or anxiety disorders.
[0036] In one embodiment, the compositions comprising the prodrugs
provided herein may be administered for the treatment of
schizophrenia or bipolar disorder or for any condition that may
require the blocking of dopamine or serotonin receptors.
[0037] The term "prodrug", as used herein, refers in one embodiment
to a metabolic precursor of a compound of the conjugated quetiapine
provided herein, which is pharmaceutically acceptable. A prodrug
may be inactive when administered to a subject but is converted in
vivo to an active compound. In one embodiment, the term "active
metabolite", refers to a metabolic product of quetiapine that is
pharmaceutically and/or pharmacologically beneficial and/or
effective. Prodrugs and active metabolites may be determined using
techniques known in the art. Prodrugs and active metabolites of a
compound may be identified using routine techniques known in the
art. In another embodiment, the term "active metabolite" refers to
a metabolic product of quetiapine that is effective for
ameliorating, treating or preventing schizophrenia, bipolar
disorder, obsessive-compulsive disorder, post-traumatic stress
disorder, restless legs syndrome, autism, alcoholism, depression,
insomnia or Tourette syndrome.
[0038] Prodrugs are often useful because, in some embodiments, they
may be easier to administer or process than the parent drug. They
may, for instance, be bioavailable by oral administration whereas
the parent is not. The prodrug may also have improved solubility in
pharmaceutical compositions over the parent drug. An embodiment of
a prodrug would be an amino acid bonded to a primary hydroxyl group
where the amino acid is metabolized to reveal the active moiety. In
certain embodiments, upon in vivo administration, a prodrug is
chemically converted to the biologically, pharmaceutically or
therapeutically more active form of the compound. In certain
embodiments, a prodrug is enzymatically metabolized by one or more
steps or processes to the biologically, pharmaceutically or
therapeutically active form of the compound. To produce a prodrug,
a pharmaceutically active compound is modified such that the active
compound will be regenerated upon in vivo administration. The
prodrug is designed to alter the metabolism or the transport
characteristics of a drug in certain embodiments, to mask
side-effects or toxicity, to improve the flavor of a drug or to
alter other characteristics or properties of a drug in other
discrete embodiments. By virtue of knowledge of pharmacodynamic
processes and drug metabolism in vivo, those of skill in this art,
once a pharmaceutically active compound is known, can design
prodrugs of the compound.
[0039] In another embodiment, the term "active metabolite" refers
to a biologically active derivative of a compound that is formed
when the compound is metabolized. The term "metabolized," refers in
one embodiment to the sum of the processes (including, but not
limited to, hydrolytic reactions and reactions catalyzed by
enzymes, such as, oxidation reactions, de-esterification reactions
and/or proteolytic reactions) by which a particular substance is
changed by an organism. Thus, enzymes may produce specific
structural alterations to a compound. In one embodiment, cytochrome
P450 catalyzes a variety of oxidative and reductive reactions while
some isoforms, such as CYP3A4 are involved in de-esterification.
Further information on metabolism may be obtained from The
Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill
(1996). Metabolites of the compounds disclosed herein can be
identified either by administration of compounds to a host under
conditions allowing for the determination of activity by the
metabolite and analysis of tissue samples from the host, or by
incubation of compounds with hepatic cells in vitro and analysis of
the resulting compounds. Both methods are well known in the art. In
some embodiments, a compound is metabolized to pharmacologically
active metabolites.
[0040] In another embodiment, amino acids conjugated to quetiapine
or its active metabolite and/or derivative create ester prodrugs
that can release the active antipsychotic. The prodrugs provided
herein alter the pharmacology and/or metabolism of quetiapine its
active metabolite and/or derivative. As a result; by choosing
suitable amino acids, the bioavailability of quetiapine is
increased. In one embodiment, the side-effect profile and
interindividual variability in plasma concentrations of the active
are improved.
[0041] In one embodiment, provided herein is a novel class of
prodrugs of quetiapine its active metabolite and/or derivative,
which is synthesized by chemically conjugating amino acids to
quetiapine its active metabolite and/or derivative. The chemical
bond between these two moieties is established by reacting the
primary hydroxyl functionality of quetiapine, its active metabolite
and/or derivative or non-binding electrons with the carboxyl group
of the amino acids, thereby creating an ester conjugate.
[0042] Accordingly and in another embodiment, provided herein is a
composition for treating a psychiatric disorder in a subject,
comprising a conjugate of
2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol
(quetiapine) its active metabolite and/or derivative and an amino
acid, a salt thereof, a derivative thereof or their
combination.
[0043] All amino acids have a core structure containing an amino
group, a carboxyl group and a distinctive side chain. The carbon
atom attached to the carboxyl group is called the .alpha.-carbon.
In .alpha.-amino acids both the amino and carboxyl group are
attached to the .alpha.-carbon. In amino acids with a carbon side
chain attached to the .alpha.-carbon, the carbons are labeled in
the order of .alpha., .beta., .gamma., .delta., .epsilon., etc.
Amino acids with the amino group attached to a carbon other than
the .alpha.-carbon are respectively called .beta.-amino acids,
.gamma.-amino acids, .delta.-amino acids and so forth. Amino acids
can be either D or L isomers. This invention includes compounds
obtained by conjugation of quetiapine to L and/or D isomers of
amino acids including but not limited to .alpha.-, .beta.-,
.gamma.-, .delta.-, .epsilon.-amino acids, standard amino acids,
non-standard amino acids, natural amino acids and synthetic
(unnatural/non-natural) amino acids.
[0044] Depending on the side chain of the amino acids conjugated to
quetiapine or its active metabolite, the prodrug formed can be
either neutral in one aspect of the invention, or free acid, free
base or pharmaceutically acceptable anionic or cationic salt forms
or salt mixtures with any ratio between positive and negative
components in other discrete aspects. These salt forms include, but
are not limited to: acetate, L-aspartate, besylate, bicarbonate,
carbonate, D-camsylate, L-camsylate, citrate, edisylate, formate,
fumarate, gluconate, hydrobromide/bromide, hydrochloride/chloride,
D-lactate, L-lactate, D,L-lactate, D,L-malate, L-malate, mesylate,
pamoate, phosphate, succinate, sulfate, bisulfate, D-tartrate,
L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate,
D-glucuronate, hybenzate, isethionate, malonate, methylsulfate,
2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate,
thiocyanate, acefyllinate, aceturate, aminosalicylate, ascorbate,
borate, butyrate, camphorate, camphocarbonate, decanoate,
hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl
sulfate, furate, fusidate, galactarate (mucate), galacturonate,
gallate, gentisate, glutamate, glutamate, glutarate,
glycerophosphate, heptanoate (enanthate), hydroxybenzoate,
hippurate, phenylpropionate, iodide, xinafoate, lactobionate,
laurate, maleate, mandelate, methanesulfonate, myristate,
napadisilate, oleate, oxalate, palmitate, picrate, pivalate,
propionate, pyrophosphate, salicylate, salicylsulfate,
sulfosalicylate, tannate, terephthalate, thiosalicylate,
tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate,
camsylate, octanoate, estolate, esylate, glycolate, thiocyanate,
and undecylenate. In one embodiment, composition for treating a
psychiatric disorder in a subject, comprising a conjugate of
2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol
(quetiapine) its active metabolite and/or derivative; and an amino
acid are in the form of a phosphate salt.
[0045] In the compositions and methods described herein, the
synthesized prodrugs are designed to breakdown enzymatically or
otherwise in vivo to quetiapine, its active metabolites and/or
derivatives and the respective amino acids or their metabolites.
Preferably, the amino acids of the present technology are Generally
Regarded As Safe (GRAS) or non-toxic at the concentrations released
into the systemic circulation.
[0046] The amino acids used in the compositions and methods
described herein, can be broadly classified in one of the following
categories: standard (proteinogenic) amino acids; non-standard
amino acids; and synthetic (unnatural/non-natural) amino acids.
Standard Amino Acids
[0047] Standard amino acids or proteinogenic amino acids include
but are not limited to the currently known 22 amino acids that make
up the monomeric units of proteins and are encoded in the standard
genetic code. Standard amino acids include alanine, arginine,
asparagine, aspartic acid, cysteine, glutamic acid, glutamine,
glycine, histidine, isoleucine, leucine, lysine, methionine,
phenylalanine, proline, pyrrolysine, selenocysteine, serine,
threonine, tryptophan, tyrosine and valine. These amino acids have
the general structure shown in FIG. 1, where R represents the side
chain on the .alpha.-carbon. In one embodiment, the compositions
provided herein, which are used in the methods provided, comprise
quetiapine or its antipsychotic-active metabolites, conjugated to a
standard amino acid, wherein the standard amino acid is alanine,
arginine, asparagine, aspartic acid, cysteine, glutamic acid,
glutamine, glycine, histidine, isoleucine, leucine, lysine,
methionine, phenylalanine, proline, pyrrolysine, selenocysteine,
serine, threonine, tryptophan, tyrosine or valine, their
derivatives and pharmaceutically acceptable salts. Accordingly and
in one embodiment, the amino acid conjugated to quetiapine or its
active metabolite, used in the compositions and methods described
herein, is an aliphatic or aromatic amino acid wherein the
aliphatic amino acid is glycine, leucine, isoleucine, proline,
valine, methionine or alanine and/or, in another embodiment the
aromatic amino acid is histidine, phenylalanine, tryptophan or
tyrosine.
Non-Standard Amino Acids
[0048] Non-standard amino acids can be found in proteins created by
chemical modifications of standard amino acids already incorporated
in the proteins. This group also includes amino acids that are not
found in proteins but are still present in living organisms.
Non-standard amino acids occur mostly as intermediates in metabolic
pathways of standard amino acids and are not encoded by the
standard genetic code. Examples of non-standard amino acids include
but are not limited to ornithine, homoarginine, citrulline,
homocitrulline, homoserine, theanine, .gamma.-aminobutyric acid,
sarcosine, cartinine, 2-aminoadipic acid, pantothenic acid,
taurine, hypotaurine, lanthionine, thiocysteine, cystathionine,
homocysteine, .beta.-amino acids such as .beta.-alanine,
.beta.-aminoisobutyric acid, .beta.-leucine, .beta.-lysine,
.beta.-arginine, .beta.-tyrosine, .beta.-phenylalanine, isoserine,
.beta.-glutamic acid, .beta.-tyrosine, .beta.-dopa
(3,4-dihydroxy-L-phenylalanine), .alpha.,.alpha.-disubstituted
amino acids such as 2-aminoisobutyric acid, isovaline,
di-n-ethylglycine, N-methyl acids such as N-methyl-alanine,
L-abrine, hydroxy-amino acids such as 4-hydroxyproline,
5-hydroxylysine, 3-hydroxyleucine, 4-hydroxyisoleucine,
5-hydroxy-L-tryptophan, cyclic amino acids such as
1-aminocyclopropyl-1-carboxylic acid, azetidine-2-carboxylic acid
and pipecolic acid (FIG. 2).
[0049] In one embodiment, the compositions provided herein, which
are used in the methods provided, comprise quetiapine or its
antipsychotic-active metabolites, conjugated to a non-standard
amino acid, wherein the non-standard amino acid is ornithine,
homoarginine, citrulline, homocitrulline, homoserine, theanine,
.gamma.-aminobutyric acid, sarcosine, cartinine, 2-aminoadipic
acid, pantothenic acid, taurine, hypotaurine, lanthionine,
thiocysteine, cystathionine, homocysteine, .beta.-amino acids such
as .beta.-alanine, .beta.-aminoisobutyric acid, .beta.-leucine,
.beta.-lysine, .beta.-arginine, .beta.-tyrosine,
.beta.-phenylalanine, isoserine, .beta.-glutamic acid,
.beta.-tyrosine, .beta.-dopa (3,4-dihydroxy-L-phenylalanine),
.alpha.,.alpha.-disubstituted amino acids such as 2-aminoisobutyric
acid, isovaline, di-n-ethylglycine, N-methyl acids such as
N-methyl-alanine, L-abrine, hydroxy-amino acids such as
4-hydroxyproline, 5-hydroxylysine, 3-hydroxyleucine,
4-hydroxyisoleucine, 5-hydroxy-L-tryptophan, cyclic amino acids
such as 1-aminocyclopropyl-1-carboxylic acid,
azetidine-2-carboxylic acid or pipecolic acid, their derivatives
and pharmaceutically acceptable salts.
Synthetic Amino Acids
[0050] Synthetic amino acids do not occur in nature and are
prepared synthetically. In another embodiment, the compositions
provided herein, which are used in the methods provided, comprise
quetiapine or its antipsychotic-active metabolites, conjugated to a
non-standard amino acid that includes but is not limited to
allylglycine, cyclohexylglycine, N-(4-hydroxyphenyl)glycine,
N-(chloroacetyl)glycine ester, 2-(trifluoromethyl)-phenylalanine,
4-(hydroxymethyl)-phenylalanine, 4-amino-phenylalanine,
2-chlorophenylglycine, 3-guanidino propionic acid,
3,4-dehydro-proline, 2,3-diaminobenzoic acid,
2-amino-3-chlorobenzoic acid, 2-amino-5-fluorobenzoic acid,
allo-isoleucine, tert-leucine, 3-phenylserine, isoserine,
3-aminopentanoic acid, 2-amino-octanedioic acid,
4-chloro-.beta.-phenylalanine, .beta.-homoproline,
.beta.-homoalanine, 3-amino-3-(3-methoxyphenyl)propionic acid,
N-isobutyryl-cysteine, 3-amino-tyrosine, 5-methyl-tryptophan,
2,3-diaminopropionic acid, 5-aminovaleric acid, and
4-(dimethylamino)cinnamic acid (FIG. 3).
[0051] In one embodiment, the compositions provided herein, which
are used in the methods provided, comprise quetiapine or its
antipsychotic-active metabolites, conjugated to a synthetic amino
acid, wherein the synthetic amino acid is allylglycine,
cyclohexylglycine, N-(4-hydroxyphenyl)glycine,
N-(chloroacetyl)glycine ester, 2-(trifluoromethyl)-phenylalanine,
4-(hydroxymethyl)-phenylalanine, 4-amino-phenylalanine,
2-chlorophenylglycine, 3-guanidino propionic acid,
3,4-dehydro-proline, 2,3-diaminobenzoic acid,
2-amino-3-chlorobenzoic acid, 2-amino-5-fluorobenzoic acid,
allo-isoleucine, tert-leucine, 3-phenylserine, isoserine,
3-aminopentanoic acid, 2-amino-octanedioic acid,
4-chloro-.beta.-phenylalanine, .beta.-homoproline,
.beta.-homoalanine, 3-amino-3-(3-methoxyphenyl)propionic acid,
N-isobutyryl-cysteine, 3-amino-tyrosine, 5-methyl-tryptophan,
2,3-diaminopropionic acid, 5-aminovaleric acid, or
4-(dimethylamino)cinnamic acid, their derivative or
pharmaceutically acceptable salt and their combination.
[0052] In one aspect of the invention any of the abovementioned
amino acids; standard (proteinogenic) amino acids; non-standard
amino acids; and synthetic (unnatural/non-natural) amino acids are
used either alone or in combination in the compositions and methods
described herein. Accordingly and in one embodiment, provided
herein is a composition for treating a psychiatric disorder in a
subject, comprising a conjugate of
2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol
(quetiapine), its active metabolite and/or derivative and their
combination; and a standard amino acid, a non-standard amino acid,
or a synthetic amino acid; a salt thereof, a derivative thereof or
their combination.
[0053] In another embodiment, the amino acid conjugated to
quetiapine, its active metabolite and/or derivative and their
combination, used in the compositions and methods described herein,
is an aliphatic amino acid, such as glycine in one embodiment. In
other embodiments the aliphatic amino acids used in the
compositions and methods described herein are leucine, isoleucine,
valine, proline, methionine or alanine each a discrete embodiment
of the aliphatic amino acids used in the conjugates of quetiapine,
its active metabolite and/or derivative and their combination
provided herein.
[0054] In one embodiment, the active metabolite of quetiapine is
N-desalkyl-quetiapine (norQTP,
4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazine):
##STR00005##
a major active human plasma metabolite of quetiapine, which has
shown in-vitro antagonistic activity on multiple brain
neurotransmitter receptors and in particular on serotonergic
(5-HT.sub.2A), noradrenergic (.alpha..sub.1-adrenoreceptor) and the
noradrenergic transporter, thus having in another embodiment, a
positive influence on mood. Likewise, N-desalkyl-quetiapine has a
high affinity for the histamine H.sub.1 receptor and moderate
affinities for the norepinephrine reuptake transporter (NET), the
serotonin 5-HT.sub.1A, 5-HT.sub.1E, 5-HT.sub.2A, 5-HT.sub.2B,
5-HT.sub.7 receptors, the .alpha..sub.1B-adrenergic receptor, and
the M.sub.1, M.sub.3, and M.sub.5 muscarinic receptors. In one
embodiment, N-desalkyl-quetiapine has about 100-fold higher avidity
for inhibiting human NET than quetiapine itself. Additionally,
N-desalkyl-quetiapine is 10-fold more potent and more efficacious
than quetiapine at the 5-HT.sub.1A receptor. N-desalkyl-quetiapine
is an antagonist at 5-HT.sub.2A, 5-HT.sub.2B, 5-HT.sub.2c,
.alpha..sub.1A, .alpha..sub.1D, .alpha..sub.2A, .alpha..sub.2C,
H.sub.1, M.sub.1, M.sub.3, and M.sub.5 receptors, with a moderate
affinity for the norepinephrine reuptake inhibitor transporter
(NET) and partial 5-HT1.sub.A agonism, indicating a significant
antidepressant effects. In one embodiment, the compositions
provided herein, which in another embodiment are used in the
methods provided herein comprise the N-desalkyl-quetiapine,
conjugated to a standard, non-standard or synthetic amino acid,
without the presence of quetiapine.
[0055] In one embodiment, the active metabolite of quetiapine is
7-hydroxy-quetiapine
(2-(2-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy-
)ethanol):
##STR00006##
another active human plasma metabolite of quetiapine having
intrinsic receptor activity. 7-hydroxy-quetiapine has been shown to
occupy dopamine D.sub.2 and serotonin 5-HT.sub.2 receptors. In one
embodiment, the compositions provided herein, which in another
embodiment are used in the methods provided herein comprise
7-hydroxy-quetiapine, conjugated to a standard, non-standard or
synthetic amino acid, without the presence of quetiapine.
[0056] In another embodiment, the term "derivative" refers to
having a substituent bonded to the quetiapine or its active
metabolite such as halogenated derivatives ether derivatives, acid
derivatives, amide derivatives, ester derivatives and the like.
Methods of preparing derivatives such as ether derivatives in one
embodiment, comprise coupling of the corresponding alcohols. In
another embodiment, the term "derivative" refers to a chemical
compound related structurally to quetiapine or its active
metabolites and is therapeutically derivable from it. In one
embodiment, the term "active derivative" refers to a derivative as
defined herein, which is accountable for a desired biological
effect. Accordingly, an active derivative of quetiapine will have
in one embodiment an antipsychotic activity, or an antidepressant
activity and the like in other embodiments of desired biological
effect.
[0057] In one embodiment, the active derivative of quetiapine is
2-chloro-N-desalkyl-quetiapine
(2-chloro-11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepine);
##STR00007##
a derivative of norQTP, which, due to its similar structure to the
known antidepressant Amoxapine (sold as ASENDIN, ASENDIS, DEFANYL,
DEMOLOX, MOXADIL), is thought to possess similar activity as a
norepinephrine reuptake inhibitor and and/or as a partial 5-HT
agonist. In one embodiment, the compositions provided herein, which
in another embodiment is used in the methods provided herein
comprise 2-chloro-N-desalkyl-quetiapine, conjugated to a standard,
non-standard or synthetic amino acid and/or its pharmaceutically
acceptable salt, without the presence of quetiapine.
[0058] In one embodiment, the active derivative of quetiapine is
4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazine,
7-hydroxy-N-desalkyl-quetiapine (7-OH-norQTP);
##STR00008##
a derivative of norQTP, which, due to its similar structure to the
known active quetiapine metabolite 7-hydroxy-quetiapine, is thought
to possess similar activity. In one embodiment, the compositions
provided herein, which in another embodiment is used in the methods
provided herein comprise 7-hydroxy-N-desalkyl-quetiapine,
conjugated to a standard, non-standard or synthetic amino acid
and/or its pharmaceutically acceptable salt, without the presence
of quetiapine.
[0059] In one embodiment, the amino acid is valine and the
conjugate is
2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethyl
L-valine,
2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy-
)ethyl D-valine,
2-(2-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)-
ethyl L-valine,
2-(2-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)-
ethyl D-valine,
(R)-2-amino-1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-3-meth-
ylbutan-1-one,
(S)-2-amino-1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-3-meth-
ylbutan-1-one,
(R)-2-amino-1-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-y-
l)-3-methylbutan-1-one,
(S)-2-amino-1-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-y-
l)-3-methylbutan-1-one; their derivative, pharmaceutically
acceptable salt or their combination.
[0060] In one embodiment, the amino acid is phenylalanine and the
conjugate is
2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethyl
L-phenylalanine,
2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethyl
D-phenylalanine,
2-(2-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)-
ethyl L-phenylalanine,
2-(2-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)-
ethyl D-phenylalanine,
(R)-2-amino-1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-3-phen-
ylpropan-1-one,
(S)-2-amino-1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-3-phen-
ylpropan-1-one,
(R)-2-amino-1-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-y-
l)-3-phenylpropan-1-one,
(S)-2-amino-1-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-y-
l)-3-phenylpropan-1-one; their derivative, pharmaceutically
acceptable salt or their combination.
[0061] Amino acid ester prodrugs of quetiapine, its active
metabolite and/or derivative and their combination as described
above can be administered orally and the parent drug is released
after hydrolysis in the body. Typically these prodrugs are easily
recognized by physiological systems because the attached amino acid
moieties are either naturally occurring or mimic naturally
occurring compounds. As a result, the prodrugs provided herein are
hydrolyzed chemically, enzymatically or by a combination of
chemical and enzymatic processes; and release quetiapine. In
another embodiment the compositions comprising the prodrug
described herein, are either pharmacologically inactive, have
pharmacological activity that is limited or different from the
parent drug, and consequently, in certain embodiments, may follow a
metabolic pathway that differs from quetiapine.
[0062] In another embodiment, the term "prodrug" refers to a
precursor or derivative form of a pharmaceutically active substance
that imparts higher bioavailability to quetiapine compared to the
parent drug and is capable of being enzymatically or hydrolytically
activated or converted into the more active parent form. In one
embodiment, the compositions comprising the prodrug described
herein would release quetiapine, its active metabolite and/or
derivative and their combination--in a similar fashion to free or
unconjugated API. In another embodiment, the compositions
comprising the prodrug described herein would release quetiapine,
its active metabolite and/or derivative or their combination--in a
controlled or sustained manner without the need of an extended
release formulation.
[0063] In a further embodiment, the compositions comprising the
prodrug described herein would have increased absorption over
unmodified quetiapine. In another embodiment, the compositions
comprising the prodrug described herein would have improved water
solubility over free quetiapine. In another embodiment, the
increased absorption over unmodified quetiapine, or improved water
solubility over free quetiapine, provide for a better
bioavailability of quetiapine referring to a higher area under the
curve (AUC) or having higher circulating plasma concentrations.
[0064] In another embodiment, conjugating quetiapine, its
therapeutically active metabolite(s) and/or derivative(s) to a
standard, nonstandard or synthetic amino acid as well as their
pharmaceutically accepted salts, alter the API metabolism, thereby
resulting in a maximum plasma concentration (C.sub.max) value of
released quetiapine that is higher than the C.sub.max value
produced by unconjugated quetiapine when administered at equimolar
doses, or in generating an AUC value of released quetiapine that is
higher than the AUC value produced by unconjugated quetiapine in
another embodiment, or in generating both a C.sub.max and an AUC
value of released quetiapine that is higher than the C.sub.max and
AUC values produced by unconjugated quetiapine, or in generating a
time after administration at which C.sub.max occurs (T.sub.max)
value of released quetiapine its active metabolite and/or
derivative and their combination that is longer than the T.sub.max
value produced by unconjugated quetiapine, or in generating a
T.sub.max value of released quetiapine that is similar to the
T.sub.max value produced by unconjugated quetiapine, when
administered at equimolar or therapeutically equivalent doses.
[0065] In one embodiment, the term "therapeutically equivalent"
refers to a preparation where its therapeutic effect is equivalent.
In another embodiment, the term "therapeutically equivalent" refers
to circumstances where conjugated quetiapine, its therapeutically
active metabolite(s) and/or derivative(s) and their
pharmaceutically acceptable salts as described herein, are
administered in amounts which give rise to the same therapeutic
effect as does the specified amount of unconjugated quetiapine, its
therapeutically active metabolite(s) and/or derivative(s) and their
pharmaceutically acceptable salts. It is routine for those skilled
in the art to determine therapeutically equivalent amounts or
dosages (see e.g. Mahatthanatrakul et al., Int J Clin Pharmacol
Ther. 2008 September; 46(9):489-96. and/or Woods, S. W. J Clin
Psychiatry. 2003 June; 64(6):663-7)
[0066] In another embodiment, the terms "therapeutically
effective", or "therapeutic effect", refers to that amount of the
conjugated or unconjugated API being administered, which will
relieve to some extent one or more of the symptoms of the disorder
or disease being treated. In another embodiment, the term
"therapeutically effective dose" refers to the amount of a compound
of the compositions described herein that, when administered to an
individual is effective to at least partially treat a disorder,
disease or condition from which the individual is suffering, or to
at least partially ameliorate a symptom of such disorder, disease
or condition. As is understood in the art, the therapeutically
effective amount of a given compound will depend at least in part
upon, the mode of administration, any carrier or vehicle (e.g.,
solution, emulsion, etc.) employed, the specific disorder or
condition, other medications taken by the individual and the
specific characteristics of the individual to whom the compound is
to be administered (age, weight, condition, sex, etc.).
[0067] In yet another embodiment, the compositions comprising the
prodrug described herein would have increased bioavailability over
unconjugated quetiapine. This may allow for administration of a
lower dose with equal or improved therapeutic effect, but with
fewer and/or less severe side-effects when compared to unmodified
quetiapine, thereby improving the safety and/or tolerability
profile of the drug. Common side-effects associated with quetiapine
include sedation, numbing, constipation, dizziness, dry mouth,
lightheadedness, nasal congestion, sore throat, stomach pain or
upset, tiredness, vomiting, weakness, weight gain, hyperlipidemia,
hypotension, hyperglycemia and more. In one embodiment, the use of
the compositions described herein results in elimination,
amelioration, reduction, delay of onset or improvement in common
side-effects associated with chronic or acute administration of
quetiapine, wherein the common side-effects include but are not
limited to sedation, constipation, dizziness, dry mouth,
lightheadedness, nasal congestion, sore throat, stomach pain or
upset, tiredness, vomiting, weakness, weight gain, hyperlipidemia,
hypotension, hyperglycemia or their combination.
[0068] In another embodiment, the compositions comprising the
prodrug described herein would reduce weight gain when compared to
unconjugated quetiapine. Accordingly and in one embodiment, the
invention provides a method of reducing weight gain resulting from
chronic or acute administration of quetiapine in a subject,
comprising the step of orally or rectally administering to the
subject a composition comprising a therapeutically effective amount
of about 1-2000 mg/dose based on equimolar weight of unconjugated
quetiapine; of quetiapine or its active metabolite and/or active
derivative thereof such as 7-hydroxy-N-desalkyl-quetiapine, or
7-hydroxy-quetiapine, conjugated to a standard amino acid such as
an aromatic or aliphatic amino acids, non-standard amino acid such
as homoarginine or synthetic amino acid, a pharmaceutically
acceptable salt such as a phosphate salt or derivative thereof,
thereby modulating leptin and/or gherlin levels, or in another
embodiment, altering the metabolism of quetiapine, its
metabolite(s) and/or derivative(s), resulting in reduced binding to
histamine receptor(s) in the subject and thereby eliminating,
reducing, delaying, decreasing and/or inhibiting weight gain in the
subject.
[0069] In one embodiment, chronic oral administration of
quetiapine, a known orexigenic, for a period of 6 weeks causes
about 37% increase in leptin release. In another embodiment,
conjugating an active metabolite and/or derivative of quetiapine to
a standard, non-standard or synthetic amino acid will decrease the
release of leptin and/or gherlin, resulting in certain embodiments
in lower weight gain or lower increase in body-mass index (BMI).
Since gherlin regulates the release of leptin in certain
embodiment, and is released in response to fasting and cachexia,
ingestion of aliphatic and aromatic amino acid conjugates of
quetiapine will decrease its release, resulting in lower weight
gain.
[0070] In one embodiment, provided herein is a method of reducing
weight gain resulting from chronic or acute administration of
quetiapine in a subject, comprising the step of orally or rectally
administering to the subject a composition comprising a
therapeutically effective amount of about 1-2000 mg/dose based on
equimolar weight of unconjugated API of a quetiapine or its active
metabolite and/or active derivative thereof such as
N-desalkyl-quetiapine, 7-hydroxy-N-desalkyl-quetiapine, or
7-hydroxy-quetiapine, conjugated to a standard amino acid such as
an aromatic or aliphatic amino acids, non-standard amino acid such
as homoarginine or synthetic amino acid, a pharmaceutically
acceptable salt thereof such as a phosphate salt, or a derivative
thereof, thereby altering the metabolism of quetiapine, its
metabolite(s) and/or derivative(s) resulting in reduced binding to
histamine receptors.
[0071] In one embodiment H.sub.1-histamine receptor antagonism
increases feeding in rodents. Additionally, in another embodiment,
depletion of neuronal histamine increases feeding. Likewise
H.sub.1-knockout mice are relatively resistant to the anorectic
actions of leptin, and are prone to obesity when placed on high-fat
diets. These results indicate that in one embodiment,
H.sub.1-histamine receptors modulate feeding behavior via a
leptin-dependent mechanism. In another embodiment, H.sub.1 affinity
is a predictor of weight gain in chronic administration of
antipsychotic. In one embodiment, the conjugated quetiapine, its
therapeutically effective metabolite(s) and/or derivative(s)
reduces the affinity of quetiapine to H.sub.1 receptor, raising the
K.sub.m in one embodiment above 11 nM.
[0072] In another embodiment, the compositions comprising the
prodrug described herein would generate a C.sub.max value of
released quetiapine that is higher than the C.sub.max value
produced by unconjugated quetiapine when administered at equimolar
doses. In a further embodiment, the compositions comprising the
prodrug described herein would generate an AUC value of released
quetiapine that is higher than the AUC value produced by
unconjugated quetiapine when administered at equimolar doses. In
yet another embodiment, the compositions comprising the prodrug
described herein would generate both a C.sub.max and an AUC value
of released quetiapine that is higher than the C.sub.max and AUC
values produced by unconjugated quetiapine when administered at
equimolar doses.
[0073] In another embodiment the compositions comprising the
prodrug described herein would generate a T.sub.max value of
released quetiapine its active metabolite and/or derivative and
their combination--that is longer than the T.sub.max value produced
by unconjugated quetiapine when administered at equimolar doses. In
another embodiment the compositions comprising the prodrug
described herein would generate a T.sub.max value of released
quetiapine that is similar to the T.sub.max value produced by
unconjugated quetiapine, when administered at equimolar doses.
[0074] In another embodiment, the compositions comprising the
prodrug described herein would have reduced interindividual
variability either due to increased bioavailability in one aspect,
or due to a modified metabolic pathway in another aspect, or due to
a combination of both in yet another aspect.
[0075] In another embodiment, the compositions comprising the
prodrug described herein would alter the metabolic pathway of the
released quetiapine when compared to unmodified quetiapine. This
new metabolism may decrease interindividual variability and/or
reduce side-effects associated with unconjugated quetiapine or any
of its metabolites, pharmaceutically acceptable salts thereof,
derivatives thereof or their combination.
[0076] In yet another embodiment, the compositions comprising the
prodrug described herein would decrease the number and/or amount of
metabolites--active, inactive, toxic or non-toxic--produced by
unmodified quetiapine. This may decrease interindividual
variability and/or reduce side-effects associated with the
administration of unconjugated quetiapine.
[0077] In a further embodiment, the compositions comprising the
prodrug described herein would increase the amount of active
metabolites when compared to unmodified quetiapine. This may
improve the therapeutic efficacy of the parent drug.
[0078] Although quetiapine is not a controlled substance, there
have been increasing reports of its misuse via oral, intranasal,
and intravenous routes to exploit its potent sedative and
anxiolytic properties. Some of its street names include "quell",
"baby heroin" and "Susie-Q". In some embodiments, the compositions
comprising the prodrug described herein may not be hydrolyzed
efficiently when administered by non-oral routes. As a result,
these prodrugs may generate plasma concentrations of released
quetiapine that are lower when compared to free quetiapine when
administered intravenously ("injected") or intranasally
("snorted").
[0079] In one embodiment, provided herein is a quetiapine or its
active metabolite, conjugated to the standard amino acid valine as
represented by any one of the structures of formulas I-IV:
##STR00009##
a pharmaceutically acceptable salt thereof, a derivative thereof or
their combination.
[0080] In another embodiment, provided herein is a quetiapine or
its active metabolite, conjugated to the standard amino acid
phenylalanine, as represented by any one of the structures of
formulas V-VIII:
##STR00010##
a pharmaceutically acceptable salt thereof, a derivative thereof or
their combination.
[0081] In one embodiment, the salt of the conjugate of quetiapine
or an active metabolite and/or derivative thereof and a standard,
non-standard and or synthetic amino acid, such as any one of the
structures represented by formulas I-VI hereinabove, is a
hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a
sulfate, a phosphate, an organic acid salt, a nitrate, or a mixture
thereof. In another embodiment, the organic acid is a mesylate
salt, a besylate salt, a tosylate salt, a benzoate, an oxalate, a
fumarate, a triflate, a citrate, a malate, or a tartarate.
Formulation Examples
[0082] The prodrugs provided in the compositions and methods herein
are primarily geared towards oral dosage forms. These dosage forms
include but are not limited to tablet, capsule, caplet, troche,
lozenge, powder, suspension, syrup, solution or oral thin film
(OTF). Embodiments of oral administration forms are capsule,
tablet, solutions and OTF. The film dosage forms provide an
inexpensive, convenient and immediate method for delivery of the
compositions described herein without the undesirable aspects
associated with certain oral or nasal delivery methods, while
providing versatility, safety and patient comfort. Any effective
edible "thin film" or "strip" may be used in accordance with the
present invention. Unless otherwise specified or required by the
context, the edible films of the present invention may be
manufactured in any effective manner.
[0083] In certain embodiments, the film layer can be produced using
a highly water-soluble polymer comprising a natural or synthetic
water-soluble polymer. The polymer preferably has good film
moldability, produces a soft flexible film, and is safe for human
consumption. In another embodiment, one such polymer can be a
water-soluble cellulose derivative like hydroxypropyl cellulose
(HPC), methyl cellulose, hydroxypropyl alkylcellulose,
carboxymethyl cellulose or the salt of carboxymethyl cellulose or
the polymer can comprise an acrylic acid copolymer or its sodium,
potassium or ammonium salt. The acrylic acid copolymer or its salt
can be combined with methacrylic acid, styrene or vinyl type of
ether as a comonomer, poly vinyl alcohol, poly vinyl pyrrolidone,
polyalkylene glycol, hydroxy propyl starch, alginic acid or its
salt, poly-saccharide or its derivatives such as tragacanth, bum
gelatin, collagen, denatured gelatin, and collagen treated with
succinic acid or anhydrous phthalic acid. In another embodiment the
powder matrix may comprise as an adhesives: poorly water-soluble
cellulose derivatives including ethyl cellulose, cellulose acetate
and butyl cellulose; shellac; higher fatty acids including steric
acid and palmitic acid. The following can also, without limitation,
be used to produce the film layer: pullulan, maltodextrin, pectin,
alginates, carrageenan, guar gum, other gelatins, etc.
The-thickness of the film layer can vary as desired, but typically
is in the range of 0.01 mm to 3.00 mm, preferably 0.03 mm to 1.00
mm. In one embodiment, the standard, non-standard, or synthetic
amino acid used in the conjugates provided herein will be affected
by the composition of the OTF.
[0084] Solid dosage forms can include the following types of
excipients: antiadherents, binders, coatings, disintegrants,
fillers, flavors, colors, glidants, lubricants, preservatives,
sorbents and sweeteners.
[0085] For oral administration, the conjugates can be formulated
readily by combining the active compounds with pharmaceutically
acceptable carriers well known in the art. Such carriers enable the
conjugates provided herein to be formulated as tablets, pills,
dragees, capsules, liquids, gels, syrups, slurries, suspensions,
and the like, for oral ingestion by a patient. Pharmacological
preparations for oral use can be made using a solid excipient,
optionally grinding the resulting mixture, and processing the
mixture of granules, after adding suitable auxiliaries if desired,
to obtain tablets or dragee cores. Suitable excipients are, in
certain embodiments, fillers such as sugars, including lactose,
sucrose, manioc, or sorbitol; cellulose preparations such as, for
example, maize starch, wheat starch, rice starch, potato starch,
gelatin, gum tragacanth, methyl cellulose,
hydroxypropylmethyl-cellulose, sodium carbomethylcellulose and/or
physiologically acceptable polymers such as poly(vinylpyrrolidone)
(PVP). If desired, in certain embodiments disintegrating agents may
be added, such as cross-linked polyvinyl pyrrolidone, agar, or
alginic acid or a salt thereof such as sodium alginate.
[0086] Dragee cores may be provided with suitable coatings. For
this purpose, concentrated sugar solutions may be used which may
optionally contain gum arabic, talc, polyvinyl pyrrolidone,
carbopol gel, polyethylene glycol, titanium dioxide, lacquer
solutions and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments may be added to the tablets or dragee
coatings for identification or to characterize different
combinations of active compound doses.
[0087] For buccal administration, the compositions may take the
form of tablets or lozenges formulated in conventional manner.
Alternatively, the active ingredient may be in powder form for
constitution with a suitable vehicle, e.g., sterile, pyrogen-free
water, before use. The conjugates provided herein may also be
formulated in rectal compositions such as suppositories or
retention enemas, using, e.g., conventional suppository bases such
as cocoa butter or other glycerides.
[0088] Pharmaceutical compositions, which can be used orally,
include push-fit capsules made of gelatin as well as soft, sealed
capsules made of gelatin and a plasticizer, such as glycerol or
sorbitol. The push-fit capsules may contain the active ingredients
in admixture with filler such as lactose, binders such as starches,
lubricants such as talc or magnesium stearate and, optionally,
stabilizers. In soft capsules, the active compounds may be
dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers may be added. All formulations for oral administration
should be in dosages suitable for the chosen route of
administration.
[0089] Quetiapine was originally launched as an immediate release
product (Seroquel.RTM.) with the following dosage strengths per
tablet: 25 mg, 50 mg, 100 mg, 200 mg and 300 mg. Recommended daily
doses typically range from 150-800 mg depending on indication and
individual patient titration. In another embodiment, quetiapine is
available in an extended release formulation (Seroquel XR.RTM.)
with dosage strengths of 50 mg, 150 mg, 200 mg, 300 mg and 400 mg
per tablet. Typical daily doses range from 300-800 mg.
[0090] In one embodiment, the conjugate of quetiapine, its
antipsychotic-active metabolite and/or active derivatives; and a
standard, non-standard, or synthetic amino acid used in the
compositions provided herein, a salt thereof, a derivative thereof
or their combination is present in an amount of between about 1 mg
and 2000 mg per dose form. In another embodiment, conjugates of
quetiapine or its antipsychotic-active metabolite and/or active
derivatives thereof, their salt or pharmaceutically acceptable salt
are present in the compositions provided herein in an amount that
is therapeutically effective. In one embodiment, conjugates of
quetiapine or its antipsychotic-active metabolite and/or active
derivatives thereof, their salt or pharmaceutically acceptable salt
are present in the compositions provided herein in an amount of
between about 150 and 800 mg per dose form. In one embodiment,
conjugates of quetiapine or its antipsychotic-active metabolite
and/or active derivatives thereof, their salt or pharmaceutically
acceptable salt are present in the compositions provided herein in
an amount of between about 1 and 100 mg per dose form, or between
about 100 and 200 mg/dose, or between about 200 and 300 mg/dose, or
between about 300 and 400 mg/dose, or between about 400 and 500
mg/dose, or between about 500 and 600 mg/dose, or between about 600
and 700 mg/dose, or between about 700 and 800 mg/dose, or between
about 800 and 900 mg/dose, or between about 900 and 1000 mg/dose,
or between about 350 and 400 mg/dose, or between about 20 and 30
mg/dose, or between about 50 and 150 mg/dose, or between about 1
and 375 mg/dose, each a discrete embodiment of the amount
conjugates of quetiapine or its antipsychotic-active metabolite
and/or active derivatives thereof, their salt or pharmaceutically
acceptable salt are present in the compositions provided herein. In
one embodiment, conjugates of quetiapine or its
antipsychotic-active metabolite and/or active derivatives thereof,
their salt or pharmaceutically acceptable salt are present in the
compositions provided herein in an amount of between about 1000 and
2000 mg per dose form. In another embodiment, conjugates of
quetiapine or its antipsychotic-active metabolite and/or active
derivatives thereof, their salt or pharmaceutically acceptable salt
are present in the compositions provided herein in an amount of
between about 1000 and 1250 mg per dose form, or between about 1250
and 1500 mg per dose form, or between about 1500 and 1750 mg per
dose form, or between about 1750 and 2000 mg per dose form, or
between about 1000 and 1500 mg per dose form, or between about 1500
and 2500 mg per dose form, in other discrete embodiments.
[0091] Doses of the amino acid-quetiapine conjugate prodrugs
described herein can be higher or lower than doses of unconjugated
quetiapine depending on their molecular weight, the respective
weight-percentage of quetiapine as part of the whole conjugate or
conjugate salt and their bioavailability (with respect to released
quetiapine). Dose conversion from quetiapine fumarate to quetiapine
prodrug are performed in one embodiment, using the following
formula:
Dose (QTP prodrug)=f.sub.BA.times.[dose(QTP
hemifumarate).times.(molecular weight(QTP prodrug)/441.95
g/mol]
Wherein:
[0092] QTP=quetiapine f.sub.BA=correction factor accounting for
differences in bioavailability between unmodified quetiapine and
the compositions comprising the prodrug described herein. This
correction factor is specific for each prodrug with
f.sub.BA.ltoreq.1 in certain embodiments. In one embodiment, the
conjugate of quetiapine, an active metabolite or derivative thereof
and a standard, non-standard and/or synthetic amino acid, a salt
thereof, a derivative thereof or their combination is present in an
amount calculated according to the formula provided herein,
referred to as "equivalent dose" to certain unconjugated quetiapine
doses.
[0093] Quetiapine is a dibenzothiazepine derivative. In
pharmacokinetic studies quetiapine is rapidly absorbed after oral
administration, with median time to reach maximum observed plasma
concentration ranging from 1 to 2 hours. Absolute bioavailability
is estimated at 9%, with a relative bioavailability from orally
administered tablets compared with a solution of almost 100%.
Administration with foods other than fatty foods, has minimal
effects on the absorption of the API. The drug is approximately 83%
bound to serum proteins. Linear pharmacokinetics are observed in
the clinical dose range (up to 375 mg twice daily). The terminal
half-life time for the drug's elimination is about 7 hours, with
the primary route of elimination being through hepatic
metabolism.
[0094] In one embodiment, the term "relative bioavailability"
refers to AUC.sub.(0-.infin.) for a specific orally administered
composition expressed as a percentage of AUC.sub.(0-.infin.) for an
orally administered formulation of the active ingredient at the
same dosage rate. The term "C.sub.max" refers to the maximum
observed blood plasma concentration or the maximum blood plasma
concentration calculated or estimated from a concentration/time
curve, and is expressed in units of ng/ml. The term "T.sub.max"
refers to the time after administration at which C.sub.max occurs,
and is expressed in units of hours (h).
[0095] In one embodiment, the relative bioavailability of the
compositions described herein is increased by between about 9 and
100% when administered orally compared with oral administration of
unconjugated quetiapine, an active metabolite and/or an active
derivative thereof. In another embodiment, the relative
bioavailability is increased by between about 25 and 100%, or
between about 50 and 100%, or between about 75 and 100%, or between
about 100 and 125%, or between about 125 and 150%, or between about
150 and 175%, or between about 175 and 200%, or between about 9 and
25%, when administered orally compared with oral administration of
unconjugated quetiapine, an active metabolite and/or an active
derivative thereof in other discrete embodiments.
[0096] Quetiapine is metabolized in one embodiment by cytochrome
P450 (CYP) 3A4 and/or 2D6 in certain other embodiments. Eleven
metabolites were identified as formed through hepatic oxidation,
with three of those found to be pharmacologically active. In one
embodiment, the metabolites are conjugated to the amino acids
described herein and are administered either alone or in
combination with the quetiapine conjugates compositions described
herein and used in the methods described. Accordingly, in one
embodiment, provided herein is a composition for treating a
psychiatric disorder in a subject, comprising a conjugate of
7-hydroxy-quetiapine (7-OH-QTP) represented by the structure of
Formula IX:
##STR00011##
and an amino acid, a salt thereof, a derivative thereof or their
combination. In another embodiment, provided herein is a
composition for treating a psychiatric disorder in a subject,
comprising a conjugate of 7-hydroxy-N-desalkyl-quetiapine
(7-OH-norQTP) represented by the structure of Formula X:
##STR00012##
and an amino acid, a salt thereof, a derivative thereof or their
combination. In another embodiment, provided herein is a
composition for treating a psychiatric disorder in a subject,
comprising a conjugate of N-desalkyl-quetiapine (norQTP)
represented by the structure of Formula XI:
##STR00013##
and an amino acid, a salt thereof, a derivative thereof or their
combination.
[0097] In one embodiment, oral clearance of unconjugated quetiapine
declines with age. In another embodiment, relative bioavailability
of amino acid-quetiapine conjugates is higher at every age, thereby
leading to reduced dosage for every indication and minimizing
side-effects. Since quetiapine is primarily metabolized by CYP3A4,
dosage adjustment may be necessary in another embodiment when
coadministered with phenytoine, thioridazine retinoic acid,
rifampicin, ketoconazole, carbamazepine or other potent CYP3A4
agonists, antagonists or modulators. In one embodiment, the choice
of amino-acid conjugated to quetiapine will affect the dosage
adjustment necessary.
Advantages
[0098] Conjugation of quetiapine or its active metabolite and/or
active derivative thereof to amino acids as described herein, has a
number of advantages that may include:
[0099] Reduced interindividual variability in plasma concentrations
vs. free quetiapine [0100] Increased bioavailability [0101]
Improved side-effect profile [0102] Less potential for toxic
metabolites [0103] Less inactive metabolites [0104] Improved
solubility [0105] Reduced potential for drug abuse
[0106] In one embodiment, the compositions comprising quetiapine
conjugated to an amino acid, further comprise a carrier, excipient,
lubricant, flow aid, processing aid or diluent, wherein said
carrier, excipient, lubricant, flow aid, processing aid or diluent
is a gum, starch, a sugar, a cellulosic material, an acrylate,
calcium carbonate, magnesium oxide, talc, lactose monohydrate,
magnesium stearate, colloidal silicone dioxide or mixtures
thereof.
[0107] In another embodiment, the composition further comprises a
binder, a disintegrant, a buffer, a protease inhibitor, a
surfactant, a solubilizing agent, a plasticizer, an emulsifier, a
stabilizing agent, a viscosity increasing agent, a sweetener, a
film forming agent, or any combination thereof.
[0108] In one embodiment, the composition is a controlled release
composition. In another embodiment, the composition is an immediate
release composition. In one embodiment, the composition is a liquid
dosage form. In another embodiment, the composition is a solid
dosage form.
[0109] In one embodiment, the term "pharmaceutically acceptable
salts" embraces salts commonly used to form alkali metal salts and
to form addition salts of free acids or free bases. The nature of
the salt is not critical, provided that it is pharmaceutically
acceptable. Suitable pharmaceutically acceptable acid addition
salts of compounds of the amino acid-quetiapine conjugates
described herein and/or their metabolites and derivatives, are
prepared in another embodiment, from an inorganic acid or from an
organic acid. Examples of such inorganic acids are hydrochloric,
hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric
acid. Appropriate organic acids may be selected from aliphatic,
cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and
sulfonic classes of organic acids, examples of which are formic,
acetic, propionic, succinic, glycolic, gluconic, lactic, malic,
tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,
aspartic, glutamic, benzoic, anthranilic, mesylic,
4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),
methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,
2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,
cyclohexylaminosulfonic, stearic, algenic, .beta.-hydroxybutyric,
salicylic, galactaric and galacturonic acid. Suitable
pharmaceutically acceptable base addition salts include metallic
salts made from aluminum, calcium, lithium, magnesium, potassium,
sodium and zinc or organic salts made from
N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and
procaine. All of these salts may be prepared by conventional means
from the corresponding compound by reacting, in another embodiment,
the appropriate acid or base with the compound.
[0110] In one embodiment, the term "pharmaceutically acceptable
carriers" includes, but is not limited to, 0.01-0.1M and preferably
0.05M phosphate buffer, or in another embodiment 0.8% saline.
Additionally, such pharmaceutically acceptable carriers may be in
another embodiment aqueous or non-aqueous solutions, suspensions,
and emulsions. Examples of non-aqueous solvents are propylene
glycol, polyethylene glycol, vegetable oils such as olive oil, and
injectable organic esters such as ethyl oleate. Aqueous carriers
include water, alcoholic/aqueous solutions, emulsions or
suspensions, including saline and buffered media. In one embodiment
the level of phosphate buffer used as a pharmaceutically acceptable
carrier is between about 0.01 to about 0.1M, or between about 0.01
to about 0.09M in another embodiment, or between about 0.01 to
about 0.08M in another embodiment, or between about 0.01 to about
0.07M in another embodiment, or between about 0.01 to about 0.06M
in another embodiment, or between about 0.01 to about 0.05M in
another embodiment, or between about 0.01 to about 0.04M in another
embodiment, or between about 0.01 to about 0.03M in another
embodiment, or between about 0.01 to about 0.02M in another
embodiment, or between about 0.01 to about 0.015 in another
embodiment.
[0111] The pharmaceutical preparations comprising the compositions
used in one embodiment in the methods provided herein can be
prepared by known dissolving, mixing, granulating, or
tablet-forming processes. For oral administration, the active
ingredients, or their physiologically tolerated derivatives in
another embodiment, such as salts, esters, N-oxides, and the like
are mixed with additives customary for this purpose, such as
vehicles, stabilizers, or inert diluents, and converted by
customary methods into suitable forms for administration, such as
tablets, coated tablets, hard or soft gelatin capsules, aqueous,
alcoholic or oily solutions. Examples of suitable inert vehicles
are conventional tablet bases such as lactose, sucrose, or
cornstarch in combination with binders such as acacia, cornstarch,
gelatin, with disintegrating agents such as cornstarch, potato
starch, alginic acid, or with a lubricant such as stearic acid or
magnesium stearate.
[0112] Examples of suitable oily vehicles or solvents are vegetable
or animal oils such as sunflower oil or fish-liver oil.
Preparations can be effected both as dry and as wet granules. For
parenteral administration (subcutaneous, intravenous,
intraarterial, or intramuscular injection), the active ingredients
or their physiologically tolerated derivatives such as salts,
esters, N-oxides, and the like are converted into a solution,
suspension, or emulsion, if desired with the substances customary
and suitable for this purpose, for example, solubilizers or other
auxiliaries. Examples are sterile liquids such as water for
injection and oils, with or without the addition of a surfactant
and other pharmaceutically acceptable adjuvants. Illustrative oils
are those of petroleum, animal, vegetable, or synthetic origin, for
example, peanut oil, soybean oil, or mineral oil. In general,
water, saline, aqueous dextrose and related sugar solutions, and
glycols such as propylene glycols or polyethylene glycol are
preferred liquid carriers, particularly for injectable solutions.
In one embodiment, using aliphatic or aromatic amino acids,
increases solubility or dispersibility of quetiapine conjugates
when compared to unconjugated quetiapine, its active metabolite
and/or derivative in the oily vehicles described herein.
[0113] In addition, the composition described in the embodiments
provided herein, can contain minor amounts of auxiliary substances
such as wetting or emulsifying agents, pH buffering agents which
enhance the effectiveness of the active ingredient.
[0114] The amino acid-quetiapine conjugate described herein is
administered in another embodiment, in a therapeutically effective
amount. The actual amount administered, and the rate and time
course of administration, will depend in one embodiment, on the
nature and severity of the condition being treated. Prescription of
treatment, e.g., decisions on dosage, timing, etc., is within the
responsibility of general practitioners or specialists, and
typically takes account of the disorder to be treated, the
condition of the individual patient, the site of delivery, the
method of administration and other factors known to practitioners.
Examples of techniques and protocols can be found in Remington's
Pharmaceutical Sciences.
[0115] The compositions of the present invention are formulated in
one embodiment for oral delivery, wherein the active compounds may
be incorporated with excipients and used in the form of ingestible
tablets, buccal tablets, troches, capsules, elixirs, suspensions,
syrups, wafers, and the like. The tablets, troches, pills, capsules
and the like may also contain the following: a sweetening agent,
such as sucrose, lactose or saccharin that may be added or a
flavoring agent, such as peppermint, oil of wintergreen, or cherry
flavoring. When the dosage unit form is a capsule, it may contain,
in addition to materials of the types described hereinabove, a
liquid carrier. Various other materials may be present as coatings
or to otherwise modify the physical form of the dosage unit. For
instance, tablets, pills, or capsules may be coated with shellac,
sugar, or both. Syrup of elixir may contain the active compound,
sucrose as a sweetening agent, methyl and propylparabens as
preservatives, a dye and flavoring, such as cherry or orange
flavor. In addition, the API may be incorporated into
sustained-release, pulsed release, controlled release or postponed
release preparations and formulations.
[0116] In another embodiment, the term "dosage unit" or "dose"
refers to the portion of a pharmaceutical composition that contains
a single unit dose of the active ingredient. For purposes of the
disclosure presented herein, a dose unit can be in the form of a
discrete article such as a tablet, capsule or a suppository, or can
be a measurable volume of a solution, suspension or the like
containing a unit dose of the active ingredient. The term "unit
dose" refers in one embodiment to an amount of active ingredient
intended for a single oral administration to a subject for
treatment of a psychiatric condition or disorder. Treatment of a
psychiatric condition or disorder, comprising mediating or binding
of a dopamine and/or serotonin and/or histamine receptor, may
require periodic administration of unit doses of the compositions
described herein, for example one unit dose two or more times a
day, one unit dose with each meal, one unit dose every four hours
or other interval, or only one unit dose per day.
[0117] Controlled or sustained release compositions include
formulations in lipophilic depots (e.g., fatty acids, waxes, oils).
Also comprehended by the invention are particulate compositions
coated with polymers (e.g., poloxamers or poloxamines).
[0118] In another embodiment, a controlled release system can be
placed in proximity to the therapeutic target, i.e., the brain,
thus requiring only a fraction of the systemic dose (see, e.g.,
Goodson, in Medical Applications of Controlled Release, supra, vol.
2, pp. 115-138 [1984]). Other controlled release systems are
discussed in the review by Langer (Science 249:1527-1533
[1990]).
[0119] In one embodiment, the carriers for use within such
compositions are biocompatible, and/or biodegradable. In other
embodiments, the formulation may provide a relatively constant
level of release of one active component. In other embodiments,
however, a more rapid rate of release immediately upon
administration may be desired. In other embodiments, release of
active compounds may be event-triggered. The events triggering the
release of the active compounds may be the same in one embodiment,
or different in another embodiment. Events triggering the release
of the active components may be exposure to moisture, lower pH or
temperature threshold in other discrete embodiments. The
formulation of such compositions is well within the level of
ordinary skill in the art using known techniques. Illustrative
carriers useful in this regard include microparticles of
poly(lactide-co-glycolide), polyacrylate, latex, starch, cellulose,
dextran and the like. Other illustrative postponed-release carriers
include supramolecular biovectors, which comprise a non-liquid
hydrophilic core (e.g., a cross-linked polysaccharide or
oligosaccharide) and, optionally, an external layer comprising an
amphiphilic compound, such as phospholipids. The amount of active
compound contained in one embodiment, within a sustained release
formulation depends upon the site of administration, the rate and
expected duration of release and the nature of the condition to be
treated suppressed or inhibited.
[0120] In one embodiment, the term "administering" refers to
bringing a subject in contact with the compositions provided
herein. For example, in one embodiment, the compositions provided
herein are suitable for oral administration, whereby bringing the
subject in contact with the composition comprises ingesting the
compositions. A person skilled in the art would readily recognize
that the methods of bringing the subject in contact with the
compositions provided herein, will depend on many variables such
as, without any intention to limit the modes of administration;
age, pre-existing conditions, other agents administered to the
subject, the severity of symptoms, subject weight or propensity to
gain weight, refraction to other medication and the like. In one
embodiment, provided herein are embodiments of methods for
administering the compounds of the present invention to a subject,
through any appropriate route, as will be appreciated by one
skilled in the art.
Methods of Synthesis
[0121] A general synthetic scheme for the synthesis of a prodrug of
this invention typically consists of the following steps: [0122] 1.
Protection of the amino acid, if applicable. [0123] 2. Activation
of the carboxylic group, if not already in activated form. [0124]
3. Addition of activated amino acid to quetiapine or vice versa in
the presence of base [0125] 4. Removal of amino acid protecting
groups, if applicable.
[0126] Accordingly and in one embodiment, provided herein is a
method of conjugating quetiapine or an active metabolite and/or
derivative thereof and an amino acid comprising the steps of: in
the presence of a base, attaching an amine-protected amino acid to
quetiapine or its active metabolite; followed by deprotecting the
amine-protected amino acid moiety, thereby, creating a carboxylic
ester between quetiapine or an active metabolite and/or derivative
thereof and a standard, non-standard or synthetic amino acid. A
schematic of an exemplary process of synthesis of a
valine-quetiapine conjugate is provided in FIG. 7.
[0127] The carboxylic acid group of the amino acid is activated in
one embodiment in order to react with quetiapine to produce
appreciable amounts of conjugate. The amino acids can be activated
in another embodiment, by synthesizing esters of N-hydroxy
succinimide (NHS). Other activating agents include but are not
limited to the following: N,N'-dicyclohexylcarbodiimide (DCC),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDCI),
N,N'-diisopropyl-carbodiimide (DIC), 1,1'-carbonyldiimidazole (CDI)
or other carbodiimides;
(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium
hexafluorophosphate (BOP), bromotripyrrolidinophosphonium
hexafluorophosphate (PyBroP),
(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate
(PyBOP) or other phosphonium-based reagents;
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU),
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU), fluoro-N,N,N',N'-tetramethylformamidinium
hexafluorophosphate (TFFH),
N,N,N',N'-tetramethyl-O--(N-succinimidyl)uronium tetrafluoroborate
(TSTU) or other ammonium-based reagents.
[0128] Accordingly and in one embodiment, provided herein is a
method of conjugating quetiapine or its active metabolite and/or
active derivative thereof and an amino acid comprising the steps
of: in the presence of a base, attaching an amine-protected amino
acid to quetiapine or its active metabolite; followed by
deprotecting the amine-protected amino acid moiety, thereby
conjugating quetiapine or an active metabolite and/or derivative
thereof and an amino acid. In one embodiment, the amine-protected
amino acid further comprises a protected side chain residue on the
amino acid.
[0129] It may be necessary to attach one or more protecting groups
to any additional reactive functional groups that may interfere
with the coupling to quetiapine. Any suitable protecting group may
be used depending on the type of functional group and reaction
conditions. The protective group may be any of those commonly used
in a process known by those skilled in the art. In one embodiment a
protective group is for an amino, thiol, hydroxy, phenol or
carboxyl group used in common preparations of amino acids. Some
protecting group examples include but are not limited to: acetyl
(Ac), tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz),
p-methoxybenzylcarbonyl (Moz), 9-fluorenylmethyloxycarbonyl (Fmoc),
benzyl (Bn), p-methoxybenzyl (PMB), 3,4 dimethoxybenzyl (DMPM),
p-methozyphenyl (PMP), tosyl (Ts), or amides (like acetamides,
pthalamides, etc). In another embodiment, the amino acid residue
protecting group is acetyl, propionyl, butyryl, phenylacetyl,
benzoyl, toluyl, POA, methoxycarbonyl, ethoxycarboryl,
2,2,2-trichloro-ethoxycarbonyl, 2-iodoethoxycarbonyl,
4-methoxybenzyloxycarbonyl,
4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr),
2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) or
2,2,5,7,8-pentamethyl-chroman-6-sulfonyl (Pmc).
[0130] In another embodiment, the protective group is not
particularly limited as long as it is a protective group known to
protect the amino group or the side chain group. Examples of useful
protective groups are those described in T. W. Greene, "Protective
groups in Organic Synthesis", A Wiley-Interscience Publication,
John-Wiley & Sons, New York, 1981, pp. 218-287. Specific
examples include but are not limited to substituted oxycarbonyl
groups, such as lower alkyloxycarbonyl groups in another
embodiment, i.e., C.sub.2-7 straight-chain or branched-chain lower
alkyloxycarbonyl groups. The protective group for carboxyl on the
group side chain is not specifically limited as long as it is a
conventional protective group known to form an ester or ether with
a carboxyl group. Examples are C.sub.1-6 straight-chain or
branched-chain substituted or unsubstituted lower alkyl groups such
as methyl, ethyl, propyl, butyl, tert-butyl, hexyl and
trichloroethyl; substituted or unsubstituted aralkyl groups such as
benzyl, p-nitrobenzyl, p-methoxybenzyl and diphenylmethyl;
acyloxyalkyl groups such as acetoxymethyl, acetoxyethyl,
propionyloxyethyl, pivaloyloxypropyl, benzoyloxymethyl,
benzoyloxyethyl, benzylcarbonyloxymethyl and
cyclohexylcarbonyloxymethyl; alkoxyalkyl groups such as
methoxymethyl, ethoxymethyl and benzyloxymethyl; and other groups
such as tetrahydropyranyl, dimethylaminoethyl, dimethylchlorosilyl
and trichlorosilyl. Preferred are substituted or unsubstituted
alkyl groups and substituted or unsubstituted aralkyl groups.
[0131] A base may be required at any step of the synthesis of amino
acid conjugates of quetiapine. Suitable bases include but are not
limited to 4-methylmorpholine (NMM), 4-(dimethylamino)pyridine
(DMAP), N,N-diisopropylethylamine, lithium
bis(trimethylsilyl)amide, lithium diisopropylamide (LDA), any
alkali metal tert-butoxide (e.g., potassium tert-butoxide), any
alkali metal hydride (e.g., sodium hydride), any alkali metal
alkoxide (e.g., sodium methoxide), triethylamine or any other
tertiary amine.
[0132] An acid may be required to remove certain protecting groups.
Suitable acids include but are not limited to hydrochloric acid,
hydrobromic acid, hydrofluoric acid, hydriodic acid, sulfuric acid,
phosphoric acid, trifluoroacetic acid, acetic acid, citric acid,
methanesulfonic acid, p-toluenesulfonic acid and nitric acid.
[0133] Appropriate solvents that can be used for any reaction in
the synthetic scheme of any amino acid conjugate of quetiapine
include but are not limited to: acetone, acetonitrile, butanol,
chloroform, dichloromethane, dimethylformamide (DMF),
dimethylsulfoxide (DMSO), dioxane, ethanol, ethyl acetate, diethyl
ether, heptane, hexane, methanol, methyl tert-butyl ether (MTBE),
isopropanol, isopropyl acetate, diisopropyl ether, tetrahydrofuran,
toluene, xylene or water.
[0134] In one embodiment, the step of deprotecting the
amine-protected amino acid moiety is preceded by a step of
deprotecting the side chain on the amino acid. In another
embodiment, the step of deprotecting the amine-protected amino
acid, is done simultaneously with deprotecting the side chain on
the amino acid. In another embodiment, the step of deprotecting the
side chain is preceded by a step of deprotecting the
amine-protected amino acid moiety.
[0135] In one embodiment, the compounds conjugated using the
methods provided herein, are used in the compositions and methods
described herein. Accordingly, and in another embodiment, provided
herein is quetiapine, its active metabolite and/or derivative;
conjugated to a standard, non-standard and/or synthetic amino acid
synthesized by attaching an amine-protected amino acid in the
presence of a base to quetiapine or its active metabolite and/or
derivative; followed by deprotecting the amine-protected amino acid
moiety, thereby conjugating quetiapine, an active metabolite and/or
an active derivative thereof and an amino acid.
[0136] In another embodiment, the protecting groups prevent
undesired or deleterious reactions from taking place at the
alpha-amino group during the formation of a new carboxyl ester bond
between the unprotected carboxyl group of the standard,
non-standard and/or synthetic amino acid; and the free non-binding
electrons on the quetiapine, its active metabolite and/or
derivative. A series of chemical steps subsequently protect the
amino acid and prepare it for coupling to the quetiapine, its
active metabolite and/or derivative without undesirable side
reactions. In one embodiment, "protecting" an acid prevents
undesired side or competing reactions, and "deprotecting" an acid
makes its functional group(s) available for a desired reaction
and/or obtaining the final conformation of the prodrug.
[0137] Deprotection is carried out in one embodiment with a mild
base treatment (e.g., picrodine or piperidine, for a non-limiting
example) for temporary protective groups, while in another
embodiment; permanent side-chain protecting groups are removed by
moderate acidolysis (e.g., trifluoroacetic acid (TFA) as a
non-limiting example).
[0138] In one embodiment, the compositions described herein are
used to carry out the methods provided herein.
[0139] In one embodiment, the psychiatric disorder sought to be
treated using the compositions provided herein is bipolar disorder
(BPD) and the inpatient receives conjugated quetiapine at an
equimolar dose in the amount of 375 mg daily of unconjugated
quetiapine, corresponding to a dose of over 375 mg daily due to the
higher bioavailability, or altered metabolism of the conjugated
quetiapine as described herein, resulting in a larger difference
and shorter duration in depressive symptoms on admission and at
discharge using the Beck-Rafaelsen Mania Scale (MAS) and/or the
Montgomery Asberg depression rating scale (MADRS),
respectively.
[0140] In another embodiment, the psychiatric disorder sought to be
treated using the compositions provided herein is schizophrenia,
and the inpatient receives conjugated quetiapine at an equimolar
dose in the amount of 450 mg daily of unconjugated quetiapine,
corresponding to a dose of over 450 mg daily due to the higher
bioavailability or altered metabolism of the conjugated quetiapine
as described herein, resulting in a larger difference and shorter
duration in psychotic symptoms on admission and at discharge using
Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression
(CGI), Positive And Negative Syndrome Scale (PANSS) and the like.
Using the compositions described herein, results in another
embodiment in increased interval between psychotic episodes,
decrease in severity of the episode and a lesser loss in cognitive
abilities following an episode.
[0141] In one embodiment, provided herein is a method of treating a
psychiatric disorder requiring the binding of dopamine receptor,
serotonin receptor, or both in a subject, comprising the step of
administering to the subject a composition comprising
therapeutically effective amount of quetiapine, an active
metabolite and/or an active derivative thereof, conjugated to an
amino acid, a pharmaceutically acceptable salt or derivative
thereof, thereby binding to a dopamine receptor, a serotonin
receptor, or both.
[0142] In another embodiment, provided herein is a method of
treating schizophrenia or bipolar disorder in a subject in need
thereof, comprising the step of administering to the subject a
composition comprising therapeutically effective amount of
quetiapine, an active metabolite and/or an active derivative
thereof, conjugated to an amino acid, a pharmaceutically acceptable
salt or derivative thereof, thereby binding to a dopamine receptor,
a serotonin receptor, or both.
[0143] In another embodiment, due to the higher relative
bioavailability the unit dose used for treating the disorders
described herein, will be adjusted downward, leading to a decrease
in number and severity of side-effects.
[0144] In one embodiment, the disorder requiring the binding of
dopamine receptor(s), serotonin receptor(s), or both in a subject
is obsessive-compulsive disorder (OCD), post-traumatic stress
disorder (PTSD), restless legs syndrome, autism, alcoholism,
depression, insomnia, hyperprolactinemia or Tourette syndrome.
[0145] By way of example, Restless Leg Syndrome (RLS) has been
treated with non-ergot dopamine agonists, with quetiapine showing
remarkable efficacy. In one embodiment, provided herein is a method
of treating RLS in a subject in need thereof, comprising the step
of orally administering to the subject a therapeutically effective
amount of a composition comprising quetiapine, an active metabolite
and/or active derivative thereof conjugated to a standard,
non-standard and/or synthetic amino acid, a pharmaceutically
acceptable salt thereof or their combination.
[0146] Likewise and in another embodiment, post-traumatic stress
disorder (PTSD) refers in one embodiment to a chronic mental
illness, causing occupational disability, psychiatric and medical
morbidity and severe psychosocial distress. The prevalence of PTSD
in the general population in the U.S. in 2006 was estimated to be
7.8%. Core symptoms of PTSD include recurrent re-experiencing of
the trauma in the form of intrusive memories, nightmares and
flashbacks; avoidant behaviors; and autonomic arousal. In addition
to the core PTSD symptoms, patients with PTSD also exhibit
irritability, impulsivity, depression and aggression. PTSD is often
difficult to treat, with recent initiatives focusing on the role of
serotonin in the neuroregulation of PTSD. The neurotransmitter
serotonin influences mood, aggression, arousal, anxiety, sleep,
learning, nociception, fear and appetite. Likewise, dopamine
neurotransmission dysfunction has been shown to be responsible for
symptoms such as paranoia, hallucinations, increased startle
response and their combination. Physiologically, the density of
platelet serotonin-uptake sites, as determined by paroxetine
binding, was significantly decreased in patients with PTSD,
compared with normal controls. Clinical studies showed the benefits
of treatment of PTSD symptoms with a 5-HT.sub.1A partial agonist,
of which quetiapine metabolite N-desalkyl-quetiapine is one.
[0147] In one embodiment, the term "treating" refers to abrogating,
substantially inhibiting, slowing or reversing the progression of a
disease, substantially ameliorating clinical symptoms of a disease
or substantially preventing or delaying the appearance of clinical
symptoms of a disease.
[0148] In one embodiment, the compositions provided herein, which
in another embodiment are used in the methods described herein; are
administered to a subject in need thereof as part of a combination
therapy with other medication that is specific for the indication
sought to be treated. A person skilled in the art would readily
recognize that combination therapy as described in the methods and
compositions provided herein, could be administered either
simultaneously or consecutively and so long as they are
administered for the same indication, would be encompassed by the
description provided herein.
[0149] Accordingly and in one embodiment lithium or divalproex in
another embodiment are used in certain embodiments as adjunct
therapies with the compositions provided herein.
[0150] In one embodiment, provided herein is the use of a
therapeutically effective amount of a conjugate of quetiapine, its
active metabolite and/or active derivative; and a standard,
non-standard and or synthetic amino acid in a medicament for the
treatment of a disorder associated with serotonin, dopamine or
histamine dysfunction in a subject in need thereof.
[0151] In the present specification, use of the singular includes
the plural except where specifically indicated.
[0152] In one embodiment, the term "subject" refers to a mammal
including a human in need of therapy for, or susceptible to, a
condition or its sequalae. The subject may include dogs, cats,
pigs, cows, sheep, goats, horses, rats, and mice and humans. The
term "subject" does not exclude an individual that is normal in all
respects.
[0153] The term "about" as used herein means in quantitative terms
plus or minus 5%, or in another embodiment plus or minus 10%, or in
another embodiment plus or minus 15%, or in another embodiment plus
or minus 20%.
[0154] The following examples are presented in order to more fully
illustrate the preferred embodiments of the invention. They should
in no way be construed, however, as limiting the broad scope of the
invention.
EXAMPLES
Example 1: Oral Pharmacokinetic Data
[0155] Plasma concentrations of quetiapine released from prodrug
conjugates as described herein were dosed as oral solutions in rats
and compared to an equimolar solution of quetiapine
dihydrochloride. Although the commercial form of quetiapine
(Seroquel.RTM.) is a fumarate salt, the dihydrochloride salt was
used as comparator because the fumarate is not soluble enough to be
dosed efficiently via oral gavage in rats.
[0156] Generally and as shown in FIGS. 4-6, plasma concentrations
of released quetiapine varied depending on the attached amino acid.
For the provided examples, the systemic exposure of released
quetiapine ranged from 99-175% (%-AUC compared to quetiapine
dihydrochloride). Valine-quetiapine showed the highest relative
%-AUC value of 175%. C.sub.max values varied between 61-189%
(%-C.sub.max compared to quetiapine dihydrochloride) with
valine-quetiapine producing the highest relative %-C.sub.max value
of 189%. T.sub.max values were similar for all examples.
Example 2: General Synthesis of Amino Acid-Quetiapine
Conjugates
[0157] A general synthetic scheme for the synthesis of a prodrug of
this invention typically consists of the following steps: [0158] 1.
Protection of the amino acid, if applicable. [0159] 2. Activation
of the carboxylic group, if not already in activated form. [0160]
3. Addition of activated amino acid to quetiapine or vice versa in
the presence of base [0161] 4. Removal of amino acid protecting
groups, if applicable.
[0162] To a solution of quetiapine (1 mmol) in THF (10 mL) was
added LiN(TMS).sub.2 (1.5 mmol) at room temperature. The solution
was stirred for 30 min. at room temperature. N-protected amino acid
succinimidyl ester (1.05 mmol) in THF (10 mL) was added dropwise.
The mixture was stirred for an additional 30 min. at room
temperature, subsequently poured into an aqueous solution of
ammonium chloride (200 mL) and extracted with EtOAc (2.times.200
mL). The organic layer was washed with aqueous NH.sub.4Cl
(2.times.100 mL) and brine (2.times.100 mL), dried over anhydrous
Na.sub.2SO.sub.4 and evaporated to dryness to yield the N-protected
amino acid-quetiapine conjugate.
[0163] The protected intermediate (1 mmol) was stirred in 4 N
HCl/dioxane (10 mL) for 30 min. at room temperature and then
concentrated to dryness to yield the respective hydrochloride salt
of the amino acid conjugate of quetiapine.
Example 3: Synthesis of Valine-Quetiapine Phosphate
(Val-QTP.H.sub.3PO.sub.4)
Boc-Val-QTP
[0164] To a solution of quetiapine free base 1 (7.66 g, 19.97 mmol)
in THF (50 mL) was added dropwise LiN(TMS).sub.2 (24.9 mL, 24.9
mmol) and the reaction mixture was stirred at room temperature for
30 min. A solution of Boc-Val-OSu (6.9 g, 21.96 mmol) in THF (12
mL) was added dropwise over a period of 3-4 min. After 1 h,
saturated aqueous NH.sub.4Cl (150 mL) was added and stirred for 15
mins. EtOAc (300 mL) was added to the reaction mixture and stirred
for an additional 30 min. The EtOAc layer was washed with citric
acid solution [2% citric acid (100 mL)+brine (100 mL)] (2.times.),
5% aq. NaHCO.sub.3 (1.times.200 mL) and brine (1.times.200 mL). The
organic phase was dried over anhydrous Na.sub.2SO.sub.4 and
evaporated to dryness to give the Boc-Val-QTP (11.09 g, 95%).
Val-QTP.3 HCl
[0165] Boc-Val-QTP was dissolved in 1.25 M HCl in IPA (150 mL) and
the reaction mixture was stirred at room temperature for 20 h. The
volume of the reaction mixture was reduced to half and poured into
IPAc (250 mL) while stirring. The precipitate was filtered, washed
with IPAc (2.times.) and dried to give Val-QTP.3 HCl (11.01 g,
98%).
Alternate Method
[0166] Boc-Val-QTP (4.5 g, 7.7 mmol) was dissolved in IPA (25 mL)
and to this solution was added 5-6 N HCl in IPA (25 mL). The brown
reaction mixture was stirred overnight at room temperature. The
reaction volume was reduced to half and poured into IPAc (150 mL)
while stirring. The white precipitate was filtered, washed with
IPAc and dried to give Val-QTP.3 HCl (4.2 g, 92%).
Val-QTP FB
[0167] Val-QTP.3 HCl (6.4 g, 10.99 mmol) was dissolved in water (50
mL) and to this solution was added saturated aq. NaHCO.sub.3 (150
mL) followed by EtOAc (250 mL). The mixture was stirred for 1 h at
room temperature. The EtOAc layer was washed with sat. NaHCO.sub.3
(2.times.) and brine, dried over Na.sub.2SO.sub.4 and evaporated to
dryness to give Val-QTP FB (5.8 g) as an oil.
Val-QTP.H.sub.3PO.sub.4
[0168] To a solution Val-QTP FB (5.8 g, 10.52 mmol) in IPA (50 mL)
was added dropwise 1 M H.sub.3PO.sub.4 solution (10.55 mL) in IPA.
A white precipitate appeared after the addition. The reaction
mixture was stirred for 30 min. at room temperature. The suspension
was diluted with IPAc (60 mL) and stirred for an additional 30 min.
The white precipitate was filtered, washed with IPAc and dried to
give Val-QTP.H.sub.3PO.sub.4 (4.05 g).
[0169] Several embodiments of exemplary valine conjugates of the
present technology are provided in FIG. 8.
Example 4: Synthesis of Phenylalanine-Quetiapine Trihydrochloride
(Phe-QTP.3 HCl)
[0170] To a solution of quetiapine free base (0.23 g, 0.6 mmol) in
THF (8 mL) was added dropwise LiN(TMS).sub.2 (0.96 mL, 0.96 mmol)
and the reaction mixture was stirred for 30 min. at room
temperature. A solution of Boc-Phe-OSu (0.228 g, 0.63 mmol) in THF
(4 mL) was added dropwise at room temperature over a period of 5
min. After 2 h, the reaction was quenched with aqueous NH.sub.4Cl
(50 mL) and stirred for 15 min. The reaction mixture was extracted
with EtOAc. The EtOAc layer was washed with aq. NH.sub.4Cl
(2.times.50 mL), sat. aq. NaHCO.sub.3 (1.times.50 mL) and brine.
The organic phase was dried over anhydrous Na.sub.2SO.sub.4 and
evaporated to dryness to give Boc-Phe-QTP (0.24 g).
[0171] Boc-Phe-QTP was dissolved in 4 N HCl/dioxane (12 mL) and the
reaction mixture was stirred for 4 h at room temperature. Solvents
were evaporated and the residue was co-evaporated with IPAc and
dried to give Phe-QTP.3 HCl (0.25 g).
[0172] Several embodiments of exemplary phenylalanine conjugates of
the present technology are provided in FIG. 9.
Example 5: Synthesis of Aspartate-Quetiapine Trihydrochloride
(Asp-QTP.3 HCl)
[0173] To a solution of quetiapine free base (0.24 g, 0.62 mmol) in
THF (8 mL) was added dropwise LiN(TMS).sub.2 (0.99 mL, 0.99 mmol)
and the reaction mixture was stirred for 30 min. at room
temperature. A solution of Boc-Asp(O.sup.tBu)-OSu (0.254 g, 0.65
mmol) in THF (4 mL) was added dropwise over a period of 5 min.
After 3 h, the reaction was quenched with aqueous NH.sub.4Cl (50
mL) and extracted with EtOAc (110 mL). The EtOAc layer was washed
with 1% aq. NaHSO.sub.4 (50 mL), sat. aq. NaHCO.sub.3 (50 mL) and
brine. The organic phase was dried over anhydrous Na.sub.2SO.sub.4
and evaporated to dryness to give Boc-Asp(O.sup.tBu)-QTP (0.265
g).
[0174] A solution of Boc-Asp(O.sup.tBu)-O-Que in 4 N HCl/dioxane
(12 mL) was stirred for 8 h at room temperature. Solvents were
evaporated and the residue was co-evaporated with IPAc and dried to
give Asp-QTP.3 HCl (0.26 g).
[0175] Having described preferred embodiments of the invention with
reference to the accompanying drawings, it is to be understood that
the invention is not limited to the precise embodiments, and that
various changes and modifications may be effected therein by those
skilled in the art without departing from the scope or spirit of
the invention as defined in the appended claims.
* * * * *